Novel compounds

ABSTRACT

The present invention relates to new CGRP-antagonists of general formula I 
     
       
         
         
             
             
         
       
     
     wherein U, V, X, Y, R 1 , R 2 , R 3  and R 4  are defined as mentioned in the description, the tautomers thereof, the isomers thereof, the diastereomers thereof, the enantiomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, medicaments containing these compounds, the use thereof and processes for the preparation thereof.

The present invention relates to new CGRP-antagonists of general formulaI

wherein U, V, X, Y, R¹, R², R³ and R⁴ are defined as mentionedhereinafter, the tautomers thereof, the isomers thereof, thediastereomers thereof, the enantiomers thereof, the hydrates thereof,the mixtures thereof and the salts thereof as well as the hydrates ofthe salts, particularly the physiologically acceptable salts thereofwith inorganic or organic acids or bases, medicaments containing thesecompounds, the use thereof and processes for the preparation thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formula I in a first embodiment

-   R¹ denotes a group of general formula II

wherein

-   G-L denotes N,N—C(R^(5.1))₂, C═C(R^(5.1)), C═N, C(R^(5.1)),    C(R^(5.1))—C(R^(5.1))₂, C(R^(5.1))—C(R^(5.1))₂—C(R^(5.1))₂,    C═C(R^(5.1))—C(R^(5.1))₂, C(R^(5.1))—C(R^(5.1))═C(R^(5.1)),    C(R^(5.1))—C(R^(5.1))₂—N(R^(5.2)), C═C(R^(5.1))—N(R^(5.2)),    C(R^(5.1))—C(R^(5.1))═N, C(R^(5.1))—N(R^(5.2))—C(R^(5.1))₂,    C═N—C(R^(5.1))₂, C(R^(5.1))—N═C(R^(5.1)),    C(R^(5.1))—N(R^(5.2))—N(R^(5.2)), C═N—N(R^(5.2)),    N—C(R^(5.1))₂—C(R^(5.1))₂, N—C(R^(5.1))═C(R^(5.1)),    N—C(R^(5.1))₂—N(R^(5.2)), N—C(R^(5.1))═N, N—N(R^(5.2))—C(R^(5.1))₂    or N—N═C(R^(5.1)),-   Q-T denotes C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶), C(R⁶)₂—C(═O),    C(═O)—C(R⁶)₂, C(R⁶)₂—S(O), or C(R⁶)₂—N(R⁶),    -   while a group C(R⁶)₂ contained in Q-T may also denote a cyclic        group, which is selected from among C₃₋₆-cycloalkyl,        C₅₋₆-cycloalkenyl or heterocyclyl, or    -   in a group C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶) contained        in Q-T in each case a group R⁶ together with an adjacent group        R⁶ and the atoms to which these groups are attached may also        denote a C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl, heterocyclyl, aryl        or heteroaryl group, which may be substituted independently of        one another by 1, 2 or 3 substituents R^(6.1),-   R² denotes    -   (a) H,    -   (b) F, —CN, C₁₋₃-alkyl, —CO₂—R^(2.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(2.1) denotes H or C₁₋₆-alkyl,-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(3.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(3.2),    -   (d) a C₅₋₇-cycloalkenyl group substituted by one or two groups        R^(3.2),    -   (e) an aryl group substituted by one or two groups R^(3.2),    -   (f) a heterocyclyl group substituted by one or two groups        R^(3.2),    -   (g) a C₅₋₇-cycloalkyl group which may be fused to an aryl or        heteroaryl group and is additionally substituted by one or two        groups R^(3.2),    -   (h) a heteroaryl group substituted by one or two groups R^(3.2),    -   (i) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.1) denotes    -   (a) H,    -   (b) an aryl group substituted by the groups R^(3.1.1) and        R^(3.1.2),    -   (c) a heteroaryl group substituted by the groups R^(3.1.1) and        R^(3.1.2),-   R^(3.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —NR^(3.1.1.1)R^(3.1.1.2), —S(O),        —C₁₋₃-alkyl, —C(O)—NR^(3.1.1.1)R^(3.1.1.2),        —O—C(O)—NR^(3.1.1.1)R^(3.1.1.2),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.1.1.1) denotes H, C₁₋₃-alkyl and-   R^(3.1.1.2) denotes H, C₁₋₃-alkyl, or-   R^(3.1.1.1) and R^(3.1.1.2) together with the nitrogen atom to which    they are attached also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(3.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(3.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —NR^(3.2.1)R^(3.2.2), —S(O)_(m)—C₁₋₃-alkyl,        —NR^(3.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(3.2.1)R^(3.2.2),        —C(O)—O—R^(3.2.3), —NR^(3.2.1)—C(O)—O—C₁₋₃-alkyl,        —O—C(O)—NR^(3.2.1)R^(3.2.2),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2.1) denotes H, C₁₋₃-alkyl and-   R^(3.2.2) denotes H, C₁₋₃-alkyl, or-   R^(3.2.1) and R^(3.2.2) together with the nitrogen atom to which    they are attached also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(3.2.3) denotes H, C₁₋₃-alkyl,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₆₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) an aryl group substituted by one or two groups R^(4.2),    -   (f) a heterocyclyl group substituted by one or two groups        R^(4.2),    -   (g) a C₆₋₇-cycloalkyl group which may be fused to an aryl or        heteroaryl group and is additionally substituted by one or two        groups R^(4.2),    -   (h) a heteroaryl group substituted by one or two groups R^(4.2),    -   (i) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(4.1) denotes    -   (a) H,    -   (b) an aryl group substituted by the groups R^(4.1.1) and        R^(4.1.2),    -   (c) a heteroaryl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —NR^(4.1.1.1)R^(4.1.1.2), —S(O)₁—C₁₋₃-alkyl,        —C(O)—NR^(4.1.1.1)R^(4.1.1.2), —O—C(O)—NR^(4.1.1.1)R^(4.1.1.2),-   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene    group is substituted by up to two fluorine atoms and each methyl    group is substituted by up to three fluorine atoms,-   R^(4.1.1.1) denotes H, C₁₋₃-alkyl and-   R^(4.1.1.2) denotes H, C₁₋₃-alkyl, or-   R^(4.1.1.1) and R^(4.1.1.2) together with the nitrogen atom to which    they are attached also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes-   (a) H,-   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,-   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group    is substituted by up to two fluorine atoms and each methyl group is    substituted by up to three fluorine atoms, or-   R^(4.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —S(O)_(m)—C₁₋₃-alkyl,        —NR^(4.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.2.1)R^(4.2.2),        —C(O)—O—R^(4.2.3), —NR^(4.2.1)—C(O)—O—C₁₋₃-alkyl,        —O—C(O)—NR^(4.2.1)R^(4.2.2,)    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.2.1) denotes H, C₁₋₃-alkyl and-   R^(4.2.2) denotes H, C₁₋₃-alkyl, or-   R^(4.2.1) and R^(4.2.2) together with the nitrogen atom to which    they are attached also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(4.2.3) denotes H, C₁₋₃-alkyl,-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote:    -   (a) a saturated 5-, 6- or 7-membered heterocyclic group, which        is substituted at a carbon atom by a group R^(4.3) or by two        groups R^(4.3) and R^(4.4),    -   (b) a saturated 5-, 6- or 7-membered heterocyclic group, which        is substituted at each of two adjacent carbon atoms by a group        R^(4.3) and R^(4.4),    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group, which        is substituted at a carbon atom by a group R^(4.3) or by two        groups R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6-        or 7-membered cycloalkyl or heterocyclyl group, while the        fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2        or 3 groups R^(4.5)    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a        phenyl group, while the fused-on phenyl group is substituted by        1, 2 or 3 groups R^(4.5),    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a 5-        or 6-membered heteroaryl group, while the fused-on heteroaryl        group is substituted by 1, 2 or 3 groups R^(4.5), or    -   (f) a heteroaryl group, which is substituted at 1, 2 or 3 carbon        atoms by a group R^(4.5) in each case,-   R^(4.3) independently of one another denote    -   (a) H, C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₆-alkynyl, aryl,        —C₁₋₃-alkylene-R^(4.3.1), C₁₋₃-alkyl-O—C(O), HO—C(O), F,        —O—C₁₋₃-alkyl, —OH, —CN,    -   (b) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (c) a 5- or 6-membered heteroaryl group,    -   (d) aryl,-   R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O—, C₁₋₃-alkyl-O—C(O)—, —CN,    —NH₂, (C₁₋₄-alkyl)-NH—, (C₁₋₄-alkyl)₂N, C₃₋₆-cycloalkyl,    heterocyclyl, heteroaryl, aryl,-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alky-l or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.3) and R^(4.4) together with the carbon atom to which they are    attached also denote a C₃₋₆-cycloalkyl-, C₅₋₆-cycloalkenyl- or    heterocyclyl group,-   R^(4.5) independently of one another denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,        —S(O)_(m)—C₁₋₃-alkyl, —NR^(4.5.2)R^(4.5.3), —CN,        —C(O)—O—R^(4.5.1), —C(O)—NR^(4.5.2)R^(4.5.3),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) aryl, heteroaryl,-   R^(4.5.1) denotes H, C₁₋₃-alkyl,-   R^(4.5.2) denotes H, C₁₋₃-alkyl,-   R^(4.5.3) denotes H, C₁₋₃-alkyl, or-   R^(4.5.2) and R^(4.5.3) together with the nitrogen atom to which    they are attached also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(5.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(5.2) denotes H or C₁₋₆-alkyl,-   R⁶ independently of one another denotes    -   (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,-   R^(6.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂—R⁷,        —C(O)—NR⁸R⁹, —O—C(O)—NR⁸R⁹, —NR⁷—C(O)—NR⁸R⁹, —NR⁸—C(O)—R⁹,        —NR⁸—C(O)—O—R⁹, —SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN,        —NR⁸R⁹, —NR⁷—C(O)—NR⁸R⁹, —O—C(O)—R⁷,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) an aryl group substituted by 1, 2 or 3 substituents R⁷,        wherein the substituents R⁷ may be identical or different,    -   (e) a heteroaryl group substituted by 1, 2 or 3 substituents R⁷,        wherein the substituents R⁷ may be identical or different,    -   (f) a heterocyclic group substituted by 1, 2 or 3 substituents        R⁷, wherein the substituents R⁷ may be identical or different,-   R^(6.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹,        —O—(CO)—NR⁸R⁹, —N(R⁷)—C(O)—NR⁸R⁹, —N(R⁸)—C(O)—R⁹,        —N(R⁸)—C(O)—O—R⁹, —SO₂—NR⁸R⁹, —N(R⁸)—SO₂—R⁹, —S(O)_(n)—R⁸, —CN,        —NR⁸R⁹, —N(R⁷)—C(O)—NR⁸R⁹, —O—C(O)—R⁷ or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁷ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl, which        may be substituted by a group R^(7.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(7.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R⁸ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl-group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁹ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        while the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R⁸ and R⁹ together may also form a ring which is selected from among    azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,    wherein the ring may be unsubstituted or substituted by 1, 2 or 3    substituents R⁷ or fluorine, wherein the substituents R⁷ are    independent of one another,-   m denotes one of the numbers 0, 1 or 2,-   s denotes one of the numbers 1, 2 or 3,-   U denotes N,N-oxide or C—R¹⁰,-   V denotes N,N-oxide or C—R¹¹,-   X denotes N,N-oxide or C—R¹²,-   Y denotes N or C—R¹³,    -   while at most three of the previously mentioned groups U, V, X        and Y simultaneously denote a nitrogen atom,-   R¹⁰ denotes H, halogen, —CN, C₁₋₃-alkyl, —CF₃, C₂₋₆-alkynyl,    HO—C₂₋₆-alkynylene,-   R¹¹ denotes H, C₁, C₁₋₃-alkyl, —NR^(11.1)R^(11.2) or —O—C₁₋₃-alkyl,-   R^(11.1) denotes H or C₁₋₆-alkyl,-   R^(11.2) denotes H or —SO₂—C₁₋₃-alkyl,-   R¹² denotes H, halogen, —CN, C₁₋₃-alkyl, —CF₃, C₂₋₆-alkynyl and-   R¹³ denotes H, halogen or C₁₋₃-alkyl,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A second embodiment of the present invention consists in the compoundsof the above general formula I, wherein U, V, X, Y, R², R³ and R⁴ are ashereinbefore defined in the first embodiment and

-   R¹ denotes a group of general formula II

wherein

-   G-L denotes N,N—C(R^(5.1))₂, C═C(R^(5.1)), C═N, C(R^(5.1)),    C(R^(5.1))—C(R^(5.1))₂, C(R^(5.1))—C(R^(5.1))₂—C(R^(5.1))₂,    C═C(R^(5.1))—C(R^(5.1) ₂, C(R^(5.1))—C(R^(5.1))═C(R^(5.1)),    C(R^(5.1))—C(R^(5.1))₂—N(R^(5.2)), C═C(R^(5.1))—N(R^(5.2)),    C(R^(5.1))—C(R^(5.1))═N, C(R^(5.1))—N(R^(5.2))—C(R^(5.1))₂,    C═N—C(R^(5.1))₂, C(R^(5.1))—N═C(R^(5.1)),    C(R^(5.1))—N(R^(5.2))—N(R^(5.2)), C═N—N(R^(5.2)),    N—C(R^(5.1))₂—C(R^(5.1))₂, N—C(R^(5.1))═C(R^(5.1)),    N—C(R^(5.1))₂—N(R^(5.2)), N—C(R^(5.1))═N, N—N(R^(5.2))—C(R^(5.1))₂    or N—N═C(R^(5.1)),-   Q-T denotes C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶), C(R⁶)₂—C(═O),    C(═O)—C(R⁶)₂, C(R⁶)₂—S(O)_(m) or C(R⁶)₂—N(R⁶),    -   while a group C(R⁶)₂ contained in Q-T may also denote a cyclic        group, which is selected from among cyclobutyl, cyclopentyl,        cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, morpholinyl,        thiomorpholinyl, thiomorpholinyl-5-oxide,        thiomorpholinyl-5-dioxide, azetidinyl, pyrrolidinyl,        piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and        piperazinyl, or    -   in a group C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶) contained        in Q-T in each case a group R⁶ together with an adjacent group        R⁶ and the atoms to which these groups are attached may also        denote a group selected from cyclobutyl, cyclopentyl,        cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, phenyl,        naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,        imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,        pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl,        isoquinolinyl, morpholinyl, thiomorpholinyl,        thiomorpholinyl-5-oxide, thiomorpholinyl-5-dioxide,        1H-quinolinyl-2-on, azetidinyl, pyrrolidinyl, piperidinyl,        tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl,        furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl, which        may be substituted independently of one another by 1, 2 or 3        substituents R^(6.1),-   R^(5.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(5.2) denotes H or C₁₋₆-alkyl,-   R⁶ independently of one another denote    -   (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,-   R^(6.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂—R⁷,        C(O)—NR⁸R⁹, —O—C(O)—NR⁸R⁹, —NR⁷—C(O)—NR⁸R⁹, —NR⁸—C(O)—R⁹,        —NR⁸—C(O)—O—R⁹, —SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN,        —NR⁸R⁹, —NR⁷—C(O)—NR⁸R⁹, —O—C(O)—R⁷,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) an aryl group substituted by 1, 2 or 3 substituents R⁷,        wherein the substituents R⁷ may be identical or different,    -   (e) a heteroaryl group substituted by 1, 2 or 3 substituents R⁷,        wherein the substituents R⁷ may be identical or different,    -   (f) a heterocyclic group substituted by 1, 2 or 3 substituents        R⁷, wherein the substituents R⁷ may be identical or different,-   R^(6.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹,        —O—(CO)—NR⁸R⁹, —N(R⁷)—C(O)—NR⁸R⁹, —N(R⁸)—C(O)—R⁹,        —N(R⁸)—C(O)—O—R⁹, —SO₂—NR⁸R⁹, —N(R⁸)—SO₂—R⁹, —S(O)_(m)—R⁸, CN,        NR⁸R⁹, —N(R⁷)—C(O)—NR⁸R⁹, —O—C(O)—R⁷ or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁷ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl, which        may be substituted by a group R^(7.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(7.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R⁸ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        while the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁹ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        while the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R⁹ and R⁹ together may also form a ring which is selected from among    azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,    wherein the ring may be unsubstituted or substituted by 1, 2 or 3    substituents R⁷ or fluorine, wherein the substituents R⁷ are    independent of one another,-   m denotes one of the numbers 0, 1 or 2 and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A third embodiment of the present invention consists in the compounds ofthe above general formula I, wherein U, V, X, Y, R², R³ and R⁴ are ashereinbefore defined in the first embodiment and

-   R¹ denotes a group of general formulae

wherein

-   Q-T denotes C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶), C(R⁶)₂—C(═O),    C(═O)—C(R⁶)₂, C(R⁶)₂—S(O)_(m) or C(R⁶)₂—N(R⁶), while in a group    C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶) contained in Q-T in each    case a group R⁶ together with an adjacent group R⁶ and the atoms to    which these groups are attached may also denote a group selected    from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,    cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl,    thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl,    imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,    pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl,    thiomorpholinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-5-dioxide,    azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,    tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl,    dihydropyranyl and piperazinyl, which may be substituted    independently of one another by 1, 2 or 3 substituents R^(6.1),-   R^(5.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁶ independently of one another denotes    -   (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,-   R^(6.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —CO₂R⁷, —C(O)NR⁸R⁹,        —SO₂—NR⁸R⁹, —N(R⁸)—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹, —O—C(O)—R⁷        or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(6.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —S(O)_(m)—R⁸, —CN,        —O—C(O)—R⁷ or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁷ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl, which        may be substituted by a group R^(7.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(7.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R⁸ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        while the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁹ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        while the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R⁹ and R⁹ together may also form a ring which is selected from among    azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,    wherein the ring may be unsubstituted or substituted by 1, 2 or 3    substituents R⁷, wherein the substituents R⁷ are independent of one    another,-   m denotes one of the numbers 0, 1 or 2 and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A fourth embodiment of the present invention consists in the compoundsof the above general formula I, wherein U, V, X, Y, R², R³ and R⁴ are ashereinbefore defined in the first embodiment and

-   R¹ denotes a group of general formulae

wherein

-   Q-T denotes C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶), C(R⁶)₂—C(═O),    C(═O)—C(R⁶)₂, C(R⁶)₂—S(O)_(m) or C(R⁶)₂—N(R⁶), while in a group    C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶) contained in Q-T in each    case a group R⁶ together with an adjacent group R⁶ and the atoms to    which these groups are attached may also denote a group selected    from cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl,    phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyridazinyl,    quinolinyl, isoquinolinyl, morpholinyl, pyrrolidinyl, piperidinyl,    tetrahydrofuranyl, tetrahydropyranyl and piperazinyl, which may be    substituted independently of one another by 1, 2 or 3 substituents    R^(6.1),-   R^(5.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁶ denotes    -   (a) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,-   R^(6.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹,        —SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹, —O—C(O)—R⁷        or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(6.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R⁷, —O—(CH₂)_(m)—OR⁷, —CO₂R⁷, —S(O)_(m)—R⁸, —CN,        —O—C(O)—R⁷ or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁷ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl, which        may be substituted by a group R⁷¹, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(7.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R⁸ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        while the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁹ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        while the groups are unsubstituted or may be substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R⁸ and R⁹ together may also form a ring which is selected from among    azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,    wherein the ring may be unsubstituted or substituted by 1, 2 or 3    substituents R⁷, wherein the substituents R⁷ are independent of one    another,-   m denotes one of the numbers 0, 1 or 2 and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A fifth embodiment of the present invention consists in the compounds ofthe above general formula I, wherein U, V, X, Y, R², R³ and R⁴ are ashereinbefore defined in the first embodiment and

-   R¹ denotes a group of general formula

wherein

-   R^(5.1) denotes    -   (a) H,    -   (b) C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁶ independently of one another denote    -   (a) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) a phenyl group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(6.2) which is selected from among benzimidazole,        benzothiophene, furan, imidazole, indole, isoxazole, oxazole,        pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,        thiazole, thiophene and triazole, wherein the substituents        R^(6.2) may be identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(6.2), wherein the substituents R^(6.2) may be        identical or different,-   R^(6.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹,        —SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹, —O—C(O)—R⁷        or (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each        methylene group is substituted by up to two fluorine atoms and        each methyl group is substituted by up to three fluorine atoms,-   R^(6.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —S(O)_(m)—R⁸, —CN,        —O—C(O)—R⁷ or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R⁷ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl, which        may be substituted by a group R^(7.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(7.1) denotes HO— or C₁₋₆-alkyl-O—,-   R⁸ denotes-   (a) H,-   (b) C₁₋₃-alkyl, phenyl or benzyl, while the groups are unsubstituted    or may be substituted by halogen, HO— or H₃C—O—,-   R⁹ denotes    -   (a) H,    -   (b) C₁₋₃-alkyl, phenyl or benzyl, while the groups are        unsubstituted or may be substituted by halogen, HO— or H₃C—O—,        or-   R⁸ and R⁹ together may also form a ring which is selected from among    azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,    while the ring may be unsubstituted or substituted by a substituent    R⁷,-   m denotes one of the numbers 0, 1 or 2, and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A sixth embodiment of the present invention consists in the compounds ofthe above general formula I, wherein U, V, X, Y, R², R³ and R⁴ are ashereinbefore defined in the first embodiment and

-   R¹ denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A seventh embodiment of the present invention consists in the compoundsof the above general formula I, wherein U, V, X, Y, R¹, R³ and R⁴ are ashereinbefore defined in the first, second, third, fourth, fifth or sixthembodiment and R² denotes a hydrogen atom,

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

An eighth embodiment of the present invention consists in the compoundsof the above general formula I, wherein U, V, X, Y, R¹ and R² are ashereinbefore defined in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl,    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(3.2),    -   (d) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₆₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) an aryl group substituted by one or two groups R^(4.2),    -   (f) a C₆₋₇-cycloalkyl group which may be fused to an aryl group        and is additionally substituted by one or two groups R^(4.2), or    -   (g) a heteroaryl group substituted by one or two groups R^(4.2),-   R^(4.1) denotes    -   (a) H,    -   (b) a phenyl group substituted by the groups R^(4.1.1) and        R^(4.1.2),    -   (c) a heteroaryl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —NR^(4.1.1.1)R^(4.1.1.2), —S—C₁₋₃-alkyl,        —NR^(4.1.1.1-)C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.1.1.1)R^(4.1.1.2),        C(O)—O—R^(4.1.1.3),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1.1.1) denotes H, C₁₋₃-alkyl,-   R^(4.1.1.2) denotes H, C₁₋₃-alkyl, or-   R^(4.1.1.1) and R^(4.1.1.2) together with the nitrogen atom to which    they are attached also denote a group selected from morpholinyl,    thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and    azetidinyl,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —NR^(4.2.1)R^(4.2.2), —S—C₁₋₃-alkyl,        —NR^(4.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.2.1)R^(4.2.2),        —C(O)—O—R^(4.2.3),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.2.1) denotes H, C₁₋₃-alkyl and-   R^(4.2.2) denotes H, C₁₋₃-alkyl, or-   R^(4.2.1) and R^(4.2.2) together with the nitrogen atom to which    they are attached also denote a group which is selected from among    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, and which may additionally be    substituted by one or two groups selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(4.2.3) denotes H, C₁₋₃-alkyl,-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote:    -   (a) a saturated 5-, 6- or 7-membered heterocyclic group, which        is substituted at a carbon atom by a group R^(4.3) or by two        groups R^(4.3) and R^(4.4),    -   (b) a saturated 5-, 6- or 7-membered heterocyclic group, which        is substituted at each of two adjacent carbon atoms by a group        R^(4.3) and R^(4.4),    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group, which        is substituted at a carbon atom by a group R^(4.3) or by two        groups R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6-        or 7-membered cycloalkyl or heterocyclyl group, while the        fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2        or 3 groups R^(4.5),    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a        phenyl group, while the fused-on phenyl group is substituted by        1, 2 or 3 groups R^(4.5),    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a 5-        or 6-membered heteroaryl group, while the fused-on heteroaryl        group is substituted by 1, 2 or 3 groups R^(4.5), or    -   (f) a heteroaryl group which is substituted at 1, 2 or 3 carbon        atoms by a group R^(4.5),-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    C₁₋₃-alkyl-O—C(O), HO—C(O), F, —O—C₁₋₃-alkyl, —OH, —CN-   R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O, cyclopropyl,    C₁₋₃-alkyl-O—C(O), CN, —NH₂, (C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N,    heterocyclyl,-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.3) and R^(4.4) together with the carbon atom to which they are    attached also denote a C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl or    heterocyclyl group,-   R^(4.5) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN,        —C(O)—O—R^(4.5.1), —C(O)—NR^(4.5.2)R^(4.5.3),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) phenyl,-   R^(4.5.1) denotes H, C₁₋₃-alkyl,-   R^(4.5.2) denotes H, C₁₋₃-alkyl and-   R^(4.5.3) denotes H, C₁₋₃-alkyl,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A ninth embodiment of the present invention consists in the compounds ofthe above general formula I, wherein U, V, X, Y, R¹ and R² are ashereinbefore defined in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl,    -   (c) a C₃₋₆-cycloalkyl substituted by one or two groups R^(3.2),        or    -   (d) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₃₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) an aryl group substituted by one or two groups R^(4.2),    -   (f) a C₃₋₆-cycloalkyl group which may be fused to a phenyl group        and which is additionally substituted by one or two groups        R^(4.2),-   R^(4.1) denotes    -   (a) H,    -   (b) a phenyl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN,        —C(O)—O—R^(4.1.13),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN,        —O—C(O)—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote:    -   (a) a saturated 5- or 6-membered heterocyclic group, which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4),    -   (b) a saturated 5- or 6-membered heterocyclic group, which is        substituted at two adjacent carbon atoms by in each case a group        R^(4.3) and R^(4.4),    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group, which        is substituted at a carbon atom by a group R^(4.3) or by two        groups R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6-        or 7-membered cycloalkyl or heterocyclyl group, while the        fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2        or 3 groups R^(4.5)    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a        phenyl group, while the fused-on phenyl group is substituted by        1, 2 or 3 groups R^(4.5),    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a 5-        or 6-membered heteroaryl group, while the fused-on heteroaryl        group is substituted by 1, 2 or 3 groups R^(4.5) and is selected        from among

-   -   (f) a heteroaryl group which is substituted at 1, 2 or 3 carbon        atoms by a group R^(4.5) in each case,

-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN

-   R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O—, cyclopropyl,    C₁₋₃-alkyl-O—C(O), CN, —NH₂, (C₁₋₄-alkyl)₂N—, morpholinyl,    thiomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl,

-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,

-   R^(4.3) and R^(4.4) together with the carbon atoms to which they are    bound also denote a C₃₋₆-cycloalkyl or heterocyclyl group, and

-   R^(4.5) independently of one another denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or    -   (d) phenyl,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof as well as the        hydrates of the salts, particularly the physiologically        acceptable salts thereof with inorganic or organic acids or        bases.

A tenth embodiment of the present invention consists in the compounds ofthe above general formula I, wherein U, V, X, Y, R¹ and R² are ashereinbefore defined in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl,    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(3.2), or    -   (d) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₅₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) a phenyl group substituted by one or two groups R^(4.2),    -   (f) a C₅₋₆-cycloalkyl group which may be fused to a phenyl group        and is additionally substituted by one or two groups R^(4.2),-   R^(4.1) denotes    -   (a) H,    -   (b) a phenyl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN,        —C(O)—O—R^(4.1.1.3),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote:    -   (a) a saturated 5- or 6-membered heterocyclic group, which is        selected from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl and pyrrolidinonyl,        and which is substituted at a carbon atom by a group R^(4.3) or        by two groups R^(4.3) and R^(4.4),    -   (b) a saturated 5- or 6-membered heterocyclic group, which is        selected from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl and pyrrolidinonyl,        and which is substituted at two adjacent carbon atoms by a group        R^(4.3) and R^(4.4) in each case,    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group, which        is selected from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl,        azepanyl, diazepanyl, diazepanonyl and oxazepanyl, and which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6- or        7-membered cycloalkyl or heterocyclyl group, which is selected        from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl,        azepanyl, diazepanyl, diazepanonyl and oxazepanyl, while the        fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2        or 3 groups R^(4.5)    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is selected from among

-   -    and which is substituted at a carbon atom by a group R^(4.3) or        by two groups R^(4.3) and R^(4.4) and is additionally fused to a        phenyl group, while the fused-on phenyl group is substituted by        1, 2 or 3 groups R^(4.5),    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group,        which is selected from among

-   -    and which is substituted at a carbon atom by a group R^(4.3) or        by two groups R^(4.3) and R^(4.4) and is additionally fused to a        5- or 6-membered heteroaryl group, while the fused-on heteroaryl        group is substituted by 1, 2 or 3 groups R^(4.5) and is selected        from among

-   -   (f) a heteroaryl group, which is selected from among indole,        isoindole, azaindole, indazole and benzimidazole, and which is        substituted at 1, 2 or 3 carbon atoms by a group R^(4.5),

-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN,

-   R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O—, cyclopropyl,    C₁₋₃-alkyl-O—C(O)—, CN, —NH₂, (C₁₋₄-alkyl)-NH—, (C₁₋₄-alkyl)₂N,    morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl,

-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,

-   R^(4.3) and R^(4.4) together with the carbon atom to which they are    attached also denote a C₃₋₆-cycloalkyl group or a heterocyclyl group    which is selected from among azetidinyl, pyrrolidinyl, piperidinyl    and azepanyl, and

-   R^(4.5) independently of one another denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or    -   (d) phenyl,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof as well as the        hydrates of the salts, particularly the physiologically        acceptable salts thereof with inorganic or organic acids or        bases.

An eleventh embodiment of the present invention consists in thecompounds of the above general formula I, wherein U, V, X, Y, R¹ and R²are as hereinbefore defined in the first, second, third, fourth, fifth,sixth or seventh embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, and-   R⁴ denotes H or a group selected from

-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A twelfth embodiment of the present invention consists in the compoundsof the above general formula I, wherein U, V, X, Y, R¹ and R² are ashereinbefore defined in the first, second, third, fourth, fifth, sixthor seventh embodiment and

-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote a monounsaturated 5-membered heterocyclic group, which is    substituted at a carbon atom by a group R^(4.3) or by two groups    R^(4.3) and R^(4.4) and is additionally fused to a phenyl group,    while the fused-on phenyl group is substituted by 1, 2 or 3 groups    R^(4.5),-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN,-   R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O, C₁₋₃-alkyl-O—C(O)—,    cyclopropyl, CN, —NH₂, (C₁₋₄-alkyl)-NH—, (C₁₋₄-alkyl)₂N,    morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl,-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.3) and R^(4.4) together with the carbon atom to which they are    attached also denote a C₃₋₆-cycloalkyl group or a heterocyclyl group    which is selected from among azetidinyl, pyrrolidinyl, piperidinyl    and azepanyl, and-   R^(4.5) independently of one another denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN, NO₂,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or    -   (d) phenyl,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof as well as the        hydrates of the salts, particularly the physiologically        acceptable salts thereof with inorganic or organic acids or        bases.

A thirteenth embodiment of the present invention consists in thecompounds of the above general formula I, wherein U, V, X, Y, R¹ and R²are as hereinbefore defined in the first, second, third, fourth, fifth,sixth or seventh embodiment and

-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote a group of general formula IIIa or IIIb

-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN,-   R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O—, C₁₋₃-alkyl-O—C(O), CN, —NH₂,    (C₁₋₄-alkyl)-NH—, (C₁₋₄-alkyl)₂N, morpholinyl, thiomorpholinyl,    piperidinyl, pyrrolidinyl, azetidinyl,-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.3) and R^(4.4) together with the carbon atom to which they are    attached also denote a C₃₋₆-cycloalkyl group or a heterocyclyl group    which is selected from among azetidinyl, pyrrolidinyl, piperidinyl    and azepanyl, and-   R^(4.5) independently of one another denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN, NO₂,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or    -   (d) phenyl,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof as well as the        hydrates of the salts, particularly the physiologically        acceptable salts thereof with inorganic or organic acids or        bases.

A fourteenth embodiment of the present invention consists in thecompounds of the above general formula I, wherein U, V, X, Y, R¹ and R²are as hereinbefore defined in the third, fifth or seventh embodimentand

-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A fifteenth embodiment of the present invention consists in thecompounds of the above general formula I, wherein R¹, R², R³ and R⁴ areas hereinbefore defined in the first, second, third, fourth, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth orfourteenth embodiment and

-   U—V—X denotes a group selected from    —N═N—(C—R¹²)═, —N═(C—R¹¹)—N═, —N═(C—R¹¹)—(C—R¹²)═,    —(N-oxide)=(C—R¹¹)—(C—R¹²)═, —(C—R¹⁰)═N—N═, —(C—R¹⁰)═N—(C—R¹²)═,    —(C—R¹⁰)═N(oxide)-(C—R¹²)═, —(C—R¹⁰)═(C—R¹¹)—N═,    —(C—R¹⁰)═(C—R¹¹)—(N-oxide)=, —(C—R¹⁰)═(C—R¹¹)—(C—R¹²)═,-   R¹⁰ denotes H, —CN,-   R¹¹ denotes H, —NR^(11.1)R^(11.2) or —O—C₁₋₃-alkyl,-   R^(11.1) denotes H or C₁₋₆-alkyl,-   R^(11.2) denotes H or —SO₂—C₁₋₃-alkyl,-   R¹² denotes H, —CN and-   Y denotes N or CH,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A further embodiment of the present invention comprises the compounds ofthe above general formula I, wherein R¹, R², R³ and R⁴ are ashereinbefore defined in the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth orfourteenth embodiment and the ring

denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A seventeenth embodiment of the present invention consists in thecompounds of general formula I wherein

-   R¹ denotes a group selected from

-   R² denotes H,-   R³ denotes    -   (a) H,    -   (b) C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, and-   R⁴ denotes H or a group selected from

-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote a group selected from

and the ring

denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

An eighteenth embodiment of the present invention consists in thecompounds of general formula I wherein

-   R¹ denotes a group selected from

-   R³ and R⁴ together with the nitrogen atom to which they are attached    denote a group selected from

and the ring

denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

The following compounds are mentioned as examples of most particularlypreferred compounds of the above general formula I:

No. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

the enantiomers, the diastereomers, the hydrates, the mixtures thereofand the salts thereof as well as the hydrates of the salts, particularlythe physiologically acceptable salts thereof with inorganic or organicacids or bases.

TERMS AND DEFINITIONS USED

The present specification of the invention is to be interpreted inaccordance with the conventions and rules of chemical bonds.

The compounds included in this invention are those that are alsochemically stable.

Unless otherwise stated, all the substituents are independent of oneanother. If for example there are a plurality of C₁₋₄-alkyl groups assubstituents in one group, in the case of three C₁₋₄-alkyl substituents,independently of one another, one may represent methyl, one ethyl andone n-propyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. If present, an asterisk (*) in the structural formula of thesubstituent is to be understood as being the linking point to the restof the molecule. For example a phenyl group is shown as follows:

Moreover, the atom of the substituent that follows the linking point isunderstood as being the atom at position number 1.

The subject-matter of this invention also includes the compoundsaccording to the invention, including the salts thereof, wherein one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

By the term “C₁₋₃-alkyl” (including those which are a part of othergroups) are meant branched and unbranched alkyl groups with 1 to 3carbon atoms, by the term “C₁₋₄-alkyl” are meant branched and unbranchedalkyl groups with 1 to 4 carbon atoms and by the term “C₁₋₆-alkyl” aremeant branched and unbranched alkyl groups with 1 to 6 carbon atoms.Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, neopentyl or n-hexyl. Theabbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionallyalso be used for the above-mentioned groups. Unless stated otherwise,the definitions propyl and butyl include all the possible isomeric formsof the groups in question. Thus, for example, propyl includes n-propyland iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are a part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₃-alkylene” are meant branched andunbranched alkylene groups with 1 to 3 carbon atoms. Examples include:methylene, ethylene, propylene, 1-methylethylene, butylene,1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene,pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene,1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless statedotherwise, the definition propylene includes all the possible isomericforms of the groups in question with the same number of carbons. Thus,for example, propyl also includes 1-methylethylene and butylene includes1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

The definition for C₀-alkylene denotes a bond.

By the term “C₂₋₆-alkenyl” (including those which are a part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theycomprise at least one double bond. Alkenyl groups with 2 to 4 carbonatoms are preferred. Examples include: ethenyl or vinyl, propenyl,butenyl, pentenyl, or hexenyl. Unless stated otherwise, the definitionspropenyl, butenyl, pentenyl and hexenyl include all the possibleisomeric forms of the groups in question. Thus, for example, propenylincludes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkynyl” (including those which are a part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theycomprise at least one triple bond. Examples include: ethynyl, propynyl,butynyl, pentynyl, or hexynyl. Unless stated otherwise, the definitionspropynyl, butynyl, pentynyl and hexynyl include all the possibleisomeric forms of the groups in question. Thus for example propynylincludes 1-propynyl and 2-propynyl, butynyl includes 1,2- and 3-butynyl,1-methyl-1-propynyl, 1-methyl-2-propynyl etc.

By the term “C₃₋₆-cycloalkyl” (including those which are a part of othergroups) are meant cyclic alkyl groups with 3 to 6 carbon atoms, by theterm “C₅₋₆-cycloalkyl” are meant cyclic alkyl groups with 5 to 6 carbonatoms and by the term “C₅₋₇-cycloalkyl” are meant cyclic alkyl groupswith 5 to 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, thecyclic alkyl groups may be substituted by one or more groups selectedfrom among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine,chlorine, bromine and iodine.

By the term “C₅₋₆-cycloalkenyl” (including those which are a part ofother groups) are meant cyclic alkenyl groups with 5 or 6 carbon atoms,which contain an unsaturated bond. Examples include: cyclopentenyl orcyclohexenyl. Unless otherwise stated, the cyclic alkenyl groups may besubstituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “heterocyclyl” or “heterocyclic group” are meant, unlessotherwise described in the definitions, stable 5-, 6- or 7-memberedmonocyclic or 8-, 9-, 10- or 11-membered bicyclic heterocyclic ringsystems which do not form an aromatic ring system in at least one ringand besides carbon atoms may carry one to four heteroatoms, which areselected from among nitrogen, oxygen and sulphur. Both nitrogen atomsand sulphur atoms may optionally be oxidised and nitrogen atoms may bequaternised. The heterocyclic ring may contain one or two carbonyl,thiocarbonyl or cyanoimino groups adjacent to a nitrogen atom. Theheterocycles mentioned previously may be attached to the rest of themolecule via a carbon atom or a nitrogen atom. Unless otherwise stated,the heterocycles may be substituted by one or more groups selected fromamong:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, COO—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

The following compounds are mentioned by way of example, but theinvention is not restricted to them: azetidine, oxetane, thietane,thietane dioxide, tetrahydrofuran, dihydrofuran, dioxolane,imidazolidine, imidazoline, imidazolidinone, dihydroimidazolone,oxazoline, oxazolidine, oxazolidinone, pyrrolidinone, dihydropyrazole,pyrrolidine, pyrroline, morpholine, tetrahydropyridine, dihydropyran,tetrahydropyran, dioxane, piperazine, piperidine, piperazinone,piperidinone, pyran, thiomorpholinyl-S-oxide, thiomorpholinyl-S-dioxide,thiomorpholine, dihydroxazine, morpholinedione, morpholinethione,perhydrothiazinedioxide, ε-caprolactam, oxazepanone, diazepanone,thiazepanone, perhydroazepine, dihydroquinazolinone, dihydroindole,dihydroisoindole, benzoxazolone, benzimidazolone, chromanone,tetrahydroquinoline, tetrahydrobenzoxazole, tetrahydrobenzisoxazole,tetrahydrobenzthiophene, tetrahydrothieno-pyridine,tetrahydrobenzofuran, tetrahydro-oxazolopyridine,tetrahydro-isoxazolopyridine.

The following heterocycles are preferred according to the invention:

By the term “aryl” (including those which are a part of other groups)are meant monocyclic aromatic ring systems with 6 carbon atoms orbicyclic aromatic ring systems with 10 carbon atoms. Examples includephenyl, 1-naphthyl or 2-naphthyl; the preferred aryl group is phenyl.

Unless otherwise stated, the aromatic groups may be substituted by oneor more groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, CO—O—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

By the term “heteroaryl” are meant stable five- or six-memberedheterocyclic aromatic groups or 8- to 10-membered bicyclic heteroarylrings that may contain in each ring one, two or three heteroatoms,selected from among oxygen, sulphur and nitrogen, and additionallysufficient conjugated double bonds to form an aromatic system. Examplesof five- or six-membered heterocyclic aromatic groups are as follows,but the invention is not restricted to these:

furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole,isothiazole, isoxazole, oxadiazole, triazole, tetrazole, furazan,thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine.

The following five-membered heterocyclic aromatic groups are preferredaccording to the invention:

The following six-membered heterocyclic aromatic groups are preferredaccording to the invention:

Examples of 9- or 10-membered bicyclic heteroaryl rings are as follows,but the invention is not restricted to these:

indole, isoindole, indazole, indolizine, benzofuran, benzothiophene,benzimidazole, benzoxazole, benzothiazole, benzotriazole, benzisoxazole,benzisothiazole, quinoline, isoquinoline, cinnoline, phthalazine,quinoxaline, quinazoline, pyridopyrimidine, pyridopyrazine,pyridopyridazine, pyrimidopyrimidine, pteridine, purine, quinolizine,benzoxazolecarbonitrile, quinoline, isoquinoline, quinolizine,pteridine, purine, quinolizine, benzoxazole-carbonitrile.

The following bicyclic heteroaryl rings are preferred according to thisinvention:

Unless otherwise stated, the heteroaryls previously mentioned may besubstituted by one or more groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, CO—O—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

Bicyclic heteroaryl rings may preferably be substituted in the phenylgroup.

By the term “halogen” are meant fluorine, chlorine, bromine or iodineatoms.

Compounds of general formula I may have acid groups, mainly carboxylgroups, and/or basic groups such as e.g. amino functions. Compounds ofgeneral formula I may therefore be present as internal salts, as saltswith pharmaceutically useable inorganic acids such as for examplehydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid,sulphuric acid, methanesulphonic acid, ethanesulphonic acid,benzenesulphonic acid, p-toluenesulphonic acid or organic acids such asfor example malic acid, succinic acid, acetic acid, fumaric acid, maleicacid, mandelic acid, lactic acid, tartaric acid, citric acid or as saltswith pharmaceutically useable bases such as alkali or alkaline earthmetal hydroxides, e.g. sodium hydroxide or potassium hydroxide, orcarbonates, ammonia, zinc or ammonium hydroxides or organic amines suchas e.g. diethylamine, triethylamine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine, inter alia.

The compounds according to the invention may be present as racemates,provided that they have only one chiral element, but may also beobtained as pure enantiomers, i.e. in the (R) or (S) form.

Compounds with a carbon-double bond may be present in both the E- andthe Z-form.

If a compound may be present in different tautomeric forms, the compoundprepared is not limited to one tautomeric form, but encompasses alltautomeric forms. This is also true in particular of nitrogen-containingheteroaryls:

However, the application also includes the individual diastereomericpairs of antipodes or mixtures thereof, which are obtained if there ismore than one chiral element in the compounds of general formula I, aswell as the individual optically active enantiomers of which theabove-mentioned racemates are made up.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable.

So-called prodrugs of compounds of general formula I are alsoencompassed by this invention. The term prodrug is used to denote anymolecule that releases the active principle of general formula I in-vivoafter administration to mammals. The prodrug may have little or nopharmacological activity per se, but releases the active principle ofgeneral formula I in-vivo after administration and this has the activitydescribed. Prodrugs for compounds of general formula I may be preparedby modifying suitable functional groups in the compound of generalformula I, as known to the skilled man in this field. (H. Bundgaard(Editor), Design of Prodrugs. (1986), Elsevier)

This invention also includes those metabolites that are derived from thecompounds of general formula I. By metabolites are meant, in thiscontext, compounds that are formed in-vivo from the compound of generalformula I after administration. Examples of metabolites include:

-   -   methyl groups of the compound of general formula I may be        converted into the corresponding hydroxymethyl groups        (—CH₃->—CH₂OH)    -   alkoxy groups of the compound of general formula I may be        converted into the corresponding hydroxyl groups (—OR->—OH)    -   secondary amines of the compound of general formula I may be        converted into the corresponding primary amines (—NR₁R₂->—NHR₁,        or —NHR₂)    -   nitrogen atoms of the compound of general formula I may be        converted into the corresponding nitrogen oxides        (═N—->═N⁺—(O⁻)—)

Methods of Preparation

The invention also relates to a process for preparing the compounds ofgeneral formula I, wherein the substituents U, V, X, Y, R¹, R², R³ andR⁴ are as hereinbefore defined.

Some methods of preparing the compounds of general formula I accordingto the invention

wherein U, V, X, Y, R¹, R², R³ and R⁴ are as hereinbefore defined, areillustrated in the following synthesis schemes and Examples.

In some cases the order of carrying out the reaction schemes may bevaried in order to simplify the reactions or prevent unwantedby-products. The Examples that follow are provided to make the inventionfully comprehensible. The Examples are intended to illustrate theinvention and should in no way restrict it.

The compounds according to the invention may be prepared according tothe schemes and specific examples provided or correspondingmodifications. Modifications to these reactions which are known to theskilled man but not described in detail here may also be implemented.

The general methods of preparing the compounds of general formula I willbe apparent to anyone skilled in the art from a study of the followingschemes.

The starting compounds are commercially available or are prepared bymethods described in the literature, known to the skilled man in thefield or described herein. Before the reaction is carried out anycorresponding functional groups in the compounds may be protected byconventional protective groups. These protective groups may be cleavedagain at a suitable stage within the reaction sequence using methodsknown in the art.

In the reactions described below, any reactive groups present such ashydroxy, carboxy, amino, alkylamino, amide or imino groups may beprotected during the reaction by conventional protective groups that arecleaved again after the reaction. For example

-   -   a suitable protective group for a hydroxy group may be the        methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl,        tert.-butyl, trityl, benzyl or tetrahydropyranyl group,    -   suitable protective groups for a carboxyl group may be the        trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl or        tetrahydropyranyl group, and    -   suitable protective groups for an amide group may be the        N-methoxymethyl-(MOM), N-benzyloxymethyl (BOM),        N-(trimethylsilyl)ethoxymethyl (SEM),        N-tert-butyldimethylsiloxymethyl, N-tert-butyldimethylsilyl        (TBDMS), N-triisopropylsilyl-(TIPS), N-benzyl, N-4-methoxybenzyl        (PMB), N-triphenylmethyl (Trt), N-tert-butoxycarbonyl (BOC),        N-benzyloxycarbonyl (Cbz) or N-trimethylsilylethylsulphonyl        (SES)    -   a suitable protective group for an amino, alkylamino or imino        group may be the acetyl, trifluoroacetyl, benzoyl,        ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl,        methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for        the amino group, the phthalyl group.

Other protective groups and their cleavage are described in T. W.Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley,1991 and 1999.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide, or by ether splitting, e.g. in thepresence of iodotrimethylsilane, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat ambient temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

A methoxy group is conveniently cleaved in the presence of borontribromide in a solvent such as methylene chloride at temperaturesbetween −35 and −25° C.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroaceticacid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxan or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxanat temperatures between 20 and 50° C.

A methoxymethyl group may be cleaved in the presence of an acid such asconcentrated hydrochloric acid in a solvent such as dimethoxyethane.Alternatively an acid such as trifluoroacetic acid may also be usedwithout a solvent.

An N-(trimethylsilyl)ethoxymethyl group may be cleaved in the presenceof TBAF and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone.Alternatively the SEM protective group may also be cleaved with an acidsuch as hydrogen chloride in an organic solvent such as dioxane orethanol.

An allyloxycarbonyl group is cleaved by treating with a catalytic amountof tetrakis-(triphenylphosphine)-palladium(0), preferably in a solventsuch as tetrahydrofuran and preferably in the presence of an excess of abase such as morpholine at temperatures between 0 and 100° C.,preferably at ambient temperature and under an inert gas, or by treatingwith a catalytic amount of tris-(triphenylphosphine)-rhodium(I) chloridein a solvent such as aqueous ethanol and optionally in the presence of abase such as 1,4-diazabicyclo[2,2,2]octane at temperatures between 20and 70° C.

The following methods of preparing the compounds of general formula Iaccording to the invention and their precursors have proved particularlysuitable:

A compound of general formula (I-3), wherein U, V, X, Y, R¹, R², R³ andR⁴ are as hereinbefore defined, may be prepared by reacting an amine oraniline of general formula (1-1), wherein R¹ and R² are as hereinbeforedefined, with an electron-poor compound of general formula (1-2),wherein U, V, X, Y, R³ and R⁴ are as hereinbefore defined and LG denotesa leaving group. Halides, preferably chlorides and bromides, —SO₂CH₃,—OSO₂CH₃, —OSO₂C₆H₄—CH₃ or —S—CH₃ (—S—CH₃ requires further reaction withan organic peroxide in order to be converted into the actual leavinggroup) etc. may act as the leaving group LG, but it is not restricted tothis list. The use of chlorides is most particularly preferred.

The reaction may be carried out by nucleophilic aromatic substitution inan inert solvent using an auxiliary base in a temperature range of from0° C. to the reflux temperature of the solvent. Nucleophilic aromaticsubstitutions are carried out in a suitable inert solvent, such astetrahydrofuran, toluene, xylene, dialkylformamide (particularlypreferably dimethylformamide), cyclic amide (particularly preferablyN-methyl-pyrrolidone), 1,4-dioxane, acetonitrile or in solvent mixtures.Suitable auxiliary bases include tertiary amines such as triethylamineor ethyldiisopropylamine, alkali metal carbonates such as potassiumcarbonate or sodium carbonate, sodium hydride (NaH) or lithiumdiisopropylamide (LDA). The inert solvent used must be compatible withthe base used. The reaction is preferably carried out indimethylformamide, at temperatures between ambient temperature and thereflux temperature of the solvent, in the presence of a tertiary aminebase.

Alternatively, structures of general formula (I-3) wherein U, V, X, Y,R¹, R², R³ and R⁴ are as hereinbefore defined may be synthesised bytransition metal-catalysed reactions. An amine or aniline of generalformula (1-1), wherein R¹ and R² are as hereinbefore defined, may reactwith a compound of general formula (1-2) wherein U, V, X, Y, R³ and R⁴are as hereinbefore defined and LG denotes a leaving group, in an inertsolvent in the presence of a catalyst and an auxiliary base. Inaddition, a suitable ligand may be used for the catalyst. Chlorides,bromides, iodides, trifluoroacetates, trifluoromethanesulphonates,methanesulphonates and toluenesulphonates may act as the leaving groupLG, but this list is not restrictive. Xylene, tetrahydrofuran,dimethylformamide, dimethoxyethane, toluene, benzene, tert-butanol,1,4-dioxane, acetonitrile or solvent mixtures may be used as inertsolvents. The preferred solvent is xylene. Suitable bases areparticularly amine bases such as e.g. triethylamine ordiisopropylethylamine or also inorganic bases such as caesium carbonate,caesium acetate, potassium carbonate, potassium-tert-butoxide, sodiumcarbonate, sodium-tert-butoxide or potassium phosphate. Preferredreaction temperatures are from RT to the reflux temperature of thesolvent at normal pressure. Typical catalysts are e.g. Transition metalcatalysts, such as e.g. palladium catalysts of thetris(dibenzylideneacetone)-dipalladium(0),tetrakis-(triphenylphosphine)-palladium(0), palladium-(II)-acetate,Pd(PPh₃)₂Cl₂, Pd(CH₃CN)₂Cl₂, Pd(dppf)Cl₂ or palladium(II)-chloride type.Typical ligands are e.g. triphenylphosphine, triphenylarsene, BINAP,XPhos, XantPhos, or 2-(di-tert-butylphosphino)biphenyl.

A compound of general formula (2-3), wherein U, V, X, Y, R¹, R², R³ andR⁴ are as hereinbefore defined, may be prepared as shown in Scheme 2 bycoupling a compound of general formula (2-2), wherein R³ and R⁴ are ashereinbefore defined, with a carboxylic acid of general formula (2-1),wherein U, V, X, Y, R¹ and R² are as hereinbefore defined, usingstandard peptide-coupling reagents and a base in an inert solvent (cf.e.g. Houben-Weyl, Methoden der Organischen Chemie, vol. 15/2).

The inert solvents used may be dimethylformamide, N-methylpyrrolidone,dimethoxyethane, dichloromethane, acetonitrile or solvent mixtures. Thepreferred solvent is dimethylformamide. Suitable bases are especiallyamine bases such as e.g. triethylamine or diisopropylethylamine.Suitable coupling reagents include for example1H-benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium-hexafluorophosphate(PyBOP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),ethyl-(3-dimethylamino-propyl)-carbodiimide,O-(1H-benzotriazol-1-yl)-N,N—N,N-tetramethyluronium-hexafluorophosphate(HBTU) or -tetrafluoroborate (TBTU) or1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium-hexafluorophosphate(BOP). It is particularly preferred to use TBTU. The activation of thecarboxyl group may alternatively also be carried out using acorresponding acid anhydride or acid chloride. The reaction is generallycarried out in a temperature range from −20° C. to the refluxtemperature of the solvent at normal pressure. Reactions are preferablycarried out at ambient temperature. The speed of the reaction can beincreased by the addition of 1-hydroxybenzotriazole (HOBt) or of3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt). Other standardcoupling conditions may also be used in the synthesis of these amides.

The compounds of general formula (3-4), wherein U, V, X, Y, R¹ and R²are as hereinbefore defined, may be synthesised either by methods knownto the skilled man or by reactions illustrated in Scheme 3 by way ofexample.

A compound of general formula (3-1), wherein R¹ and R² are ashereinbefore defined, may be reacted with an electron-poor compound ofgeneral formula (3-2), wherein U, V, X and Y are as hereinbefore definedand LG denotes a leaving group. Halides, preferably chlorides andbromides, —SO₂CH₃, —OSO₂CH₃, —OSO₂C₆H₄—CH₃ or —S—CH₃ (—S—CH₃ requiresfurther reaction with an organic peroxide in order to be converted intothe actual leaving group) etc. may act as the leaving group LG, but itis not restricted to this list. The use of chlorides is mostparticularly preferred. The reaction may be carried out in an inertsolvent using an auxiliary base in a temperature range from 0° C. to thereflux temperature of the solvent. The inert solvent may betetrahydrofuran, toluene, xylene, dialkylformamide (dimethylformamide isparticularly preferred), cyclic amide (N-methylpyrrolidone isparticularly preferred), 1,4-dioxane, acetonitrile or solvent mixtures.Suitable auxiliary bases are especially tertiary amines such astriethylamine or ethyldiisopropylamine and alkali metal carbonates suchas potassium carbonate or sodium carbonate. Preferably the reaction iscarried out in dimethylformamide, at temperatures between ambienttemperature and the reflux temperature of the solvent, in the presenceof a tertiary amine base.

Esters of general formula (3-3), wherein U, V, X, Y, R¹ and R² are ashereinbefore defined, may be converted by basic or acid hydrolysis (J.March, Advanced Organic Chemistry (New York: J. Wiley and Sons, 1985) orby reaction with alkali metal salts (preferably Lil or NaCN) in an inertsolvent into the acid of general formula (3-4). Inert solvents may bedialkylformamide (N,N-dimethylformamide is particularly preferred),dialkylacetamide (N,N-dimethylacetamide is particularly preferred),cyclic amide (N-methylpyrrolidone is particularly preferred). Alkalinesaponification with alkali metal hydroxides such as sodium hydroxide orlithium hydroxide in inert solvents is particularly preferred. Suitableinert solvents are water and cyclic ethers such as 1,4-dioxane ortetrahydrofuran as well as solvent mixtures.

The compounds of general formula (4-3), wherein U, V, X, Y, R³ and R⁴are as hereinbefore defined and LG denotes a leaving group, may besynthesised analogously to Scheme 4.

Carboxylic acid halides of general formula (4-1), wherein U, V, X and Yare as hereinbefore defined, LG denotes a leaving group, for example ahalide, and Hal denotes a chlorine or bromine, may be reacted withcompounds of general formula (4-2), wherein R³ and R⁴ are ashereinbefore defined. The reaction may be carried out in an inertsolvent or without a solvent. Similarly, the reaction may also becarried out with or without a base. The inert solvents used may behalogen-containing hydrocarbons (the use of dichloromethane ordichloroethane is particularly preferred), dialkylethers (diethyl etheris preferred), cyclic ethers (1,4-dioxane or tetrahydrofuran ispreferred) and aromatic hydrocarbons. Bases that may be used aretertiary amines (triethylamine or diisopropylethylamine is preferred)and aromatic amines (pyridine is preferred).

The compounds of general formula (5-3) wherein U, V, X, Y, R³ and R⁴ areas hereinbefore defined and LG denotes a leaving group may besynthesised analogously to Scheme 5.

Carboxylic acids of general formula (5-1), wherein U, V, X and Y are ashereinbefore defined and LG denotes a leaving group, may be reacted withcompounds of general formula (5-2), wherein R³ and R⁴ are ashereinbefore defined, using standard peptide coupling reagents and abase in an inert solvent to form amides of general formula (5-3),wherein U, V, X, Y, R³ and R⁴ are as hereinbefore defined and LG denotesa leaving group (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie,vol. 15/2). Halides, preferably chlorides and bromides, —SO₂CH₃,—OSO₂CH₃, —OSO₂C₆H₄—CH₃ or —S—CH₃ (—S—CH₃ requires further reaction withan organic peroxide in order to be converted into the actual leavinggroup) may act as the leaving group LG, but it is not restricted to thislist. The use of chlorides is most particularly preferred. The inertsolvents used may be dimethylformamide, N-methylpyrrolidone,dimethoxyethane, dichloromethane, acetonitrile or solvent mixtures. Thepreferred solvent is dimethylformamide. Suitable bases are especiallyamine bases such as e.g. triethylamine or diisopropylethylamine.Suitable coupling reagents include for example1H-benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium-hexafluorophosphate(PyBOP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),ethyl-(3-dimethylamino-propyl)-carbodiimide,O-(1H-benzotriazol-1-yl)-N,N—N,N-tetramethyl-uronium-hexafluorophosphate(HBTU) or -tetrafluoroborate (TBTU) or1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium-hexafluorophosphate(BOP). Particularly preferred is the use of TBTU. The activation of thecarboxyl group may also be carried out using a corresponding acidanhydride or acid chloride. The reaction is generally carried out in atemperature range from −20° C. to the reflux temperature of the solventat normal pressure. Particularly preferred is the use ofdiisopropylethylamine as base and dimethylformamide as solvent.

Compounds of general formula (6-3), wherein U, V, X, Y, Wand R² are ashereinbefore defined, may be prepared analogously to Scheme 6.

Here, a compound of general formula (6-1), wherein U, V, X, Y, R¹ and R²are as hereinbefore defined and LG denotes a leaving group, may bereacted with an alcohol and carbon monoxide in the presence of acatalyst and an auxiliary base. A suitable ligand may additionally beused for the catalyst. Chlorides, bromides, iodides, trifluoroacetates,trifluoromethanesulphonates, methanesulphonates and toluenesulphonatesmay serve as the leaving group LG, but this list is not restrictive. Thealcohols used are preferably methanol and ethanol, but this list is notrestrictive. Suitable bases are especially amine bases such as e.g.triethylamine or diisopropylethylamine or also inorganic bases such ascaesium carbonate, caesium acetate, potassium carbonate,potassium-tert-butoxide, sodium carbonate, sodium acetate,sodium-tert-butoxide or potassium phosphate. Typical catalysts are e.g.transition metal catalysts, such as e.g. palladium catalysts such astris(dibenzylideneacetone)-dipalladium(0),tetrakis-(triphenylphosphine)-palladium(0), palladium-(II)-acetate,Pd(PPh₃)₂Cl₂, Pd(CH₃CN)₂Cl₂, Pd(dppf)Cl₂ or palladium(II)-chloride.Typical ligands are e.g. triphenylphosphine, tricyclohexylphosphine,tri-(tert-butyl)phosphine, 1,4-bis(diphenylphosphino)butane (dppb),1,1′-bis(diphenylphosphino)ferrocene (dppf),1,3-bis(diisopropylphosphino)-propane,1,3-bis(diphenylphosphino)propane(dppp),1,4-bis(dicyclohexylphosphino)butane,1,1″-bis(dicyclohexylphosphino)ferrocene. The pressure of carbonmonoxide in the reaction vessel is from 1 bar to 100 bar, while elevatedcarbon monoxide pressures of 10 to 30 bar are preferred. The reactionsmay be carried out in a temperature range from RT to 200° C.Particularly preferred is a temperature range from 100° C. to 150° C.(M. Beller, W. Magerlein, A. F. Indolese, Ch. Fischer, Synthesis (2001)7, 1098-1109 and literature cited therein). Esters of general formula(6-2), wherein U, V, X, Y, R¹ and R² are as hereinbefore defined andalkyl denotes a C₁₋₃-alkyl group, may be converted by basic or acidhydrolysis (J. March, Advanced Organic Chemistry (New York: J. Wiley andSons, 1985) or by reaction with alkali metal salts (preferably Lil orNaCN) in an inert solvent into the acid of general formula (6-3). Inertsolvents may be dialkylformamides (N,N-dimethylformamide is particularlypreferred), dialkylacetamides (N,N-dimethylacetamide is particularlypreferred), cyclic amides (N-methylpyrrolidone is particularlypreferred). Alkaline saponification with alkali metal hydroxides such assodium hydroxide or lithium hydroxide in inert solvents is particularlypreferred. Suitable inert solvents are water and cyclic ethers such as1,4-dioxane or tetrahydrofuran as well as solvent mixtures.

In some cases the end product may be further derivatised, e.g. bymanipulation of the substituents. These manipulations may be, interalia, those which are generally known to the skilled man, such asoxidation, reduction, alkylation, acylation and hydrolysis, but need notbe restricted to the above.

The new compounds of general formula I according to the invention maycontain one or more chiral centres. If for example there are two chiralcentres present, the compounds may occur in the form of twodiastereomeric pairs of antipodes. The invention includes the individualisomers as well as the mixtures thereof.

The diastereomers may be separated on the basis of their differentphysico-chemical properties, e.g. by fractional crystallisation fromsuitable solvents, by high pressure liquid or column chromatography,using chiral or preferably non-chiral stationary phases.

Racemates covered by general formula I may be separated for example byHPLC on suitable chiral stationary phases (e.g. Chiral AGP, ChiralpakAD). Racemates which contain a basic or acidic function can also beseparated via the diastereomeric, optically active salts which areproduced on reacting with an optically active acid, for example (+) or(−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or(−)-monomethyl tartrate or (+) or (−)-camphorsulphonic acid, or anoptically active base, for example with (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemateof a compound of general formula I is reacted with one of theabovementioned optically active acids or bases in equimolar amounts in asolvent and the resulting crystalline, diastereomeric, optically activesalts thereof are separated using their different solubilities. Thisreaction may be carried out in any type of solvent provided that it issufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof, for example in aratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralised with a base such assodium carbonate or potassium carbonate, or with a suitable acid, e.g.with dilute hydrochloric acid or aqueous methanesulphonic acid, and inthis way the corresponding free compound is obtained in the (+) or (−)form.

The (R) or (S) enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formula I may also beobtained by performing the syntheses described above with a suitablereaction component in the (R) or (S) configuration.

The new compounds of general formula I and the physiologicallyacceptable salts thereof have valuable pharmacological properties, basedon their selective CGRP-antagonistic properties. The invention furtherrelates to pharmaceutical compositions containing these compounds, theiruse and the preparation thereof.

The new compounds mentioned above and the physiologically acceptablesalts thereof have CGRP-antagonistic properties and exhibit goodaffinities in CGRP receptor binding studies. The compounds displayCGRP-antagonistic properties in the pharmacological test systemsdescribed hereinafter.

The following experiments were carried out to demonstrate the affinityof the above-mentioned compounds for human CGRP-receptors and theirantagonistic properties:

A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRPReceptor)

SK-N-MC membranes (˜20 μg protein) are incubated for 180 minutes atambient temperature with 50 pM ¹²⁵I-iodotyrosyl-Calcitonin-Gene-RelatedPeptide and increasing concentrations of the test substances in a totalvolume of 250 μl (assay buffer: 10 mM tris, 50 mM NaCl, 5 mM MgCl₂, 1 mMEDTA, pH=7.4). The incubation is ended by rapid filtration throughGF/B-glass fibre filters treated with polyethyleneimine (0.1%) using acell harvester. The protein-bound radioactivity is measured using agamma counter. Non-specific binding is defined as the boundradioactivity after the presence of 1 μM BIBN4096BS during incubation.

The concentration binding curves are analysed using computer-aidednon-linear curve fitting.

The compounds mentioned hereinbefore show K_(i) values ≦50 μm in thetest described.

B. CGRP Antagonism in SK-N-MC Cells

SK-N-MC cells (1000 cells per well) are incubated for 30 minutes in thepresence of increasing concentrations of CGRP and differentconcentrations of the test substance.

The cAMP contents of the samples are determined using an AlphaScreencAMP assay kit (Perkin Elmer) and the pA₂ values of antagonisticallyacting substances are determined graphically.

The compounds according to the invention exhibit CGRP-antagonisticproperties in the in vitro test model described, in a dosage rangebetween 10⁻¹² and 10⁻⁴ M.

To demonstrate that the compounds of general formula I exhibit good tovery good CGRP-antagonistic activities with different structuralelements, the following Table gives the K_(i) values obtained accordingto the test procedure described above. It should be noted that thecompounds were selected for their different structural elements and notin order to emphasise specific compounds:

Example K_(i) [nM]  (8) 4 (11) 34 (15) 21 (17) 117 (36) 5 (37) 2 (41) 21(50) 690 (55) 3

Indications

In view of their pharmacological properties the compounds according tothe invention and the salts thereof with physiologically acceptableacids are thus suitable for the acute and prophylactic treatment ofheadaches, particularly migraine or cluster headaches and tensionheadaches. Moreover, the compounds according to the invention also havea positive effect on the following diseases: non-insulin-dependentdiabetes mellitus (“NIDDM”), cardiovascular diseases, morphinetolerance, diarrhoea caused by clostridium toxin, skin diseases,particularly thermal and radiation-induced skin damage includingsunburn, lichen, pruritis, pruritic toxidermies and severe itching,inflammatory diseases, e.g. inflammatory diseases of the joints(osteoarthritis, rheumatoid arthritis, neurogenic arthritis),generalised soft-tissue rheumatism (fibromyalgia), neurogenicinflammation of the oral mucosa, inflammatory lung diseases, allergicrhinitis, asthma, COPD, diseases accompanied by excessive vasodilatationand resultant reduced blood supply to the tissues, e.g. shock andsepsis, chronic pain, e.g. diabetic neuropathies, neuropathies inducedby chemotherapy, HIV-induced neuropathies, postherpetic neuropathies,neuropathies induced by tissue trauma, trigeminal neuralgias,temporomandibular dysfunctions, CRPS (complex regional pain syndrome),back pain, and visceral complaints, such as e.g. irritable bowelsyndrome (IBS) and inflammatory bowel syndrome. In addition, thecompounds according to the invention have a general pain-relievingeffect. The symptoms of menopausal hot flushes caused by vasodilatationand increased blood flow in oestrogen-deficient women andhormone-treated patients with prostate carcinoma and castrated men arefavourably affected by the CGRP antagonists of the present applicationin a preventive and acute-therapeutic capacity, this therapeuticapproach being distinguished from hormone replacement by the absence ofside effects.

The dosage required to achieve a corresponding effect is conveniently0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of bodyweight, when administered intravenously or subcutaneously, and 0.01 to10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight whenadministered orally, nasally or by inhalation, 1 to 3× a day in eachcase.

If the treatment with CGRP antagonists and/or CGRP release inhibitors isgiven as a supplement to conventional hormone replacement, it isadvisable to reduce the doses specified above, in which case the dosagemay be from 1/5 of the lower limits mentioned above up to 1/1 of theupper limits specified.

The invention further relates to the use of the compounds according tothe invention as valuable adjuvants for the production and purification(by affinity chromatography) of antibodies as well as in RIA and ELISAassays, after suitable radioactive labelling, for example by tritiationof suitable precursors, for example by catalytic hydrogenation withtritium or replacing halogen atoms with tritium, and as a diagnostic oranalytical adjuvant in neurotransmitter research.

Combinations

Categories of active substance which may be used in combination includee.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokininantagonists, anticonvulsants, histamine-H1-receptor antagonists,β-blockers, α-agonists and α-antagonists, ergot alkaloids, mildanalgesics, non-steroidal antiphlogistics, corticosteroids, calciumantagonists, 5-HT_(1B/1D)-agonists or other anti-migraine agents whichmay be formulated together with one or more inert conventional carriersand/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions, solutions, metered dose aerosols or suppositories.

Thus other active substances which may be used for the combinationsmentioned above include for example the non-steroidal antiinflammatoriesaceclofenac, acemetacin, acetyl-salicylic acid, acetaminophen(paracetamol), azathioprine, diclofenac, diflunisal, fenbufen,fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen,leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone,piroxicam, sulphasalazine, zomepirac or the pharmaceutically acceptablesalts thereof as well as meloxicam and other selective COX2-inhibitors,such as for example rofecoxib, valdecoxib, parecoxib, etoricoxib andcelecoxib, as well as substances that inhibit earlier or later stages ofprostaglandin synthesis or prostaglandin receptor antagonists such ase.g. EP2-receptor antagonists and IP-receptor antagonists.

It is also possible to use ergotamine, dihydroergotamine,metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine,chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox,gabapentin, pregabalin, duloxetine, topiramate, riboflavin, montelukast,lisinopril, micardis, prochloroperazine, dexamethasone, flunarizine,dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol,atenolol, clonidine, indoramin, carbamazepine, phenyloin, valproate,amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem and other5-HT_(1B/1D)-agonists such as, for example, almotriptan, avitriptan,eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan andzolmitriptan.

Furthermore, CGRP antagonists with vanilloid receptor antagonists, suchas e.g. VR-1 antagonists, glutamate receptor antagonists, such as e.g.MGlu5 receptor antagonists, mGlu1 receptor antagonists, iGlu5 receptorantagonists, AMPA receptor antagonists, purine receptor blockers, suchas e.g. P2X3 antagonists, NO-synthase inhibitors, such as e.g. INOSinhibitors, calcium channel blockers, such as e.g. PQ-type blockers,N-type blockers, potassium channel openers, such as e.g. KCNQ channelopeners, sodium channel blockers, such as e.g. PN3 channel blockers,NMDA receptor antagonists, acid-sensing ion channel antagonists, such ase.g. ASIC3 antagonists, bradykinin receptor antagonists such as e.g. B1receptor antagonists, cannabinoid receptor agonists, such as e.g. CB2agonists, CB1 agonists, somatostatin receptor agonists, such as e.g.Sst2 receptor agonists may be added.

The dosage of these active substances is expediently 1/5 of the lowestusually recommended dose to 1/1 of the normally recommended dose, i.e.for example 20 to 100 mg of sumatriptan.

Formulations

The compounds prepared according to the invention may be administeredeither on their own or optionally in combination with other activesubstances for the treatment of migraine by intravenous, subcutaneous,intramuscular, intraarticular, intrarectal, intranasal route, byinhalation, topically, transdermally or orally, while aerosolformulations are particularly suitable for inhalation. The combinationsmay be administered either simultaneously or sequentially.

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formula I according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula I areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula I are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula I have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Experimental Section

As a rule IR, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. Unless stated otherwise, R_(f) values are determinedusing ready-made TLC silica gel plates 60 F254 (E. Merck, Darmstadt,Item no. 1.05714) without chamber saturation.

The ratios given for the eluants relate to units by volume of theparticular solvents. The units by volume given for NH₃ relate to aconcentrated solution of NH₃ in water. Eluant systems used for TLC:

-   -   eluant A: DCM/cyclohexane/MeOH/NH₄OH=70/15/15/2    -   eluant B: petroleum ether/ethyl acetate=2/1

Unless stated otherwise, the acid, base and salt solutions used inworking up the reaction solutions are aqueous systems of the specifiedconcentrations. Silica gel made by Millipore (MATREX™, 35-70 μm) is usedfor chromatographic purifications. The HPLC data provided are measuredunder the parameters listed below and using the columns mentioned:

Columns Used:

(column temperature: 30° C.; injection volume: 5 μL; detection at 254nm)

S1 Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 3.5 μm;4.6 × 75 mm S2 Waters Sunfire, SB (Stable Bond) C18; 3.5 μm; 4.6 × 75 mmS3 Agilent Bonus C18; 5 μm, 4.6 × 75 mm S4 Zorbax column (AgilentTechnologies), SB (Stable Bond) C18; 1.8 μm; 3.0 × 30 mm S5 Zorbaxcolumn (Agilent Technologies), SB (Stable Bond) C18; 5 μm; 4.6 × 75 mmS6 Waters Symmetry C18; 3.5 μm; 4.6 × 75 mm S7 Waters XBridge C18; 3.5μm; 4.6 × 75 mm (basic column) S8 WatersSunfire C18; 2.5 μm; 3.0 × 30 mm

Solvents Used:

-   -   for the columns S1 to S6 (acid conditions) the following        solvents were used:        solvent A: water (with 0.1% formic acid)        solvent B: acetonitrile (with 0.1% formic acid)    -   for the column S7 (basic conditions) the following solvents were        used:        solvent A: water (with 0.1% NH₄OH)        solvent B: acetonitrile (with 0.1% NH₄OH)        (the percentages given relate to the total volume)

Gradients:

gradient time (flow) [min] % A % B G1 0.0 95 5 (0.8 mL/min) 8.0 50 509.0 10 90 10.0 10 90 11.0 95 5 time gradient [min] % A % B G2 0.00 95 5(1.6 mL/min) 0.10 95 5 1.75 5 95 1.90 5 95 1.95 95 5 2.00 95 5 timegradient [min] % A % B G3 0.00 95 5 (1.6 mL/min) 4.50 10 90 5.00 10 905.50 95 5 time gradient [min] % A % B G4 0.00 95 5 (1.6 mL/min) 4.00 5050 4.50 10 90 5.00 10 90 5.50 95 5 time gradient [min] % A % B G5 0.0090 10 (1.6 mL/min) 4.50 10 90 5.50 10 90 gradient time (flow) [min] % A% B G6 0.0 95 5 (0.8 mL/min) 9.0 10 90 10.0 10 90 11.0 95 5 timegradient [min] % A % B G7 0.00 95 5 (1.6 mL/min) 2.00 50 50 2.25 10 902.50 10 90 2.75 95 5

Methods:

column gradient method A S1 G4 method B S2 G4 method C S4 G2 method D S6G4 method E S1 G3 method F S3 G3 method G S5 G4 method H S1 G5 method KS2 G3 method L S1 G2 method M S7 G3 method N S2 G1 method O S2 G6 methodQ S5 G5 method R S4 G7 method S S8 G7

In preparative HPLC purifications, the products are collected eitherunder mass control or by UV detection. The fractions containing productare combined and freeze-dried. The following columns may be used forpreparative HPLC separations:

S8 Agilent Zorbax SB C18, 50 × 150 mm, 5 μm S9 Agilent Zorbax StableBond, 50 × 140 mm, 7 μm S10 Waters Sunfire C18, 30 × 100 mm, 5 μm S11Waters Symmetry 50 × 140 mm, 7 μm S12 Agilent Zorbax Stable Bond C18, 30× 100 mm, 5 μm,

The Following Solvent Systems May be Used for the Preparative HPLCSeparation:

-   -   solvent A: water (with 0.1% formic acid)    -   solvent B: acetonitrile (with 0.1% formic acid)    -   solvent A: water (with 0.15% formic acid)    -   solvent B: acetonitrile (with 0.15% formic acid)    -   solvent A: water (with 0.3% formic acid)    -   solvent B: acetonitrile    -   solvent A: water (with 0.3% formic acid)    -   solvent B: acetonitrile (with 0.3% formic acid)    -   solvent A: water (with 0.1% NH₄OH)    -   solvent B: acetonitrile (with 0.1% NH₄OH)

The percentages given relate in each case to the total volume.

In the absence of any more information regarding the configuration, itis unclear whether there are pure enantiomers involved or whetherpartial or even total racemisation has taken place.

The following abbreviations are used in the test descriptions:

-   ACN acetonitrile-   AcOH acetic acid-   BINAP 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl-   BOC tert.-butyloxycarbonyl-   CAD circulating air dryer-   CDI 1,1′-carbonyldiimidazole-   CO carbon monoxide-   conc. concentrated-   Cyc cyclohexane-   DC drying cupboard-   DCM dichloromethane-   DIPE diisopropylether-   DIPEA diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMF N,N-dimethylformamide-   dppf 1,1′-bis-(diphenylphosphino)ferrocene-   of theoretical of theory-   d-water deionised water-   El electron jet ionisation (in MS)-   Eq equivalent-   ESI electrospray ionisation (in MS)-   EtOAc ethyl acetate-   EtOH ethanol-   GWM General Working Method-   HATU    [dimethylamino-(1,2,3-triazolo[4,5-b]pyridin-3-yloxy)-methylen]-dimethyl-ammonium-hexafluorophosphate-   HCl hydrogen chloride-   HPLC High Performance Liquid Chromatography-   HPLC-MS HPLC coupled mass spectrometry-   i.vac. in vacuo (under vacuum)-   MeOH methanol-   MS mass spectrometry-   MW molecular weight [g/mol]-   NaOAc sodium acetate-   NaOH sodium hydroxide-   NH₄OH ammonium hydroxide (aqueous ammonia solution, 30%)-   NMP N-methyl-2-pyrrolidine-   Pd/C palladium on charcoal-   Pd₂ dba₃ bis(dibenzylideneacetone) palladium (0)-   PE petroleum ether-   R_(f) retention index (bei DC)-   RT ambient temperature-   R_(t) retention time (in HPLC)-   TBME tert.-butyl-methylether-   TBTU O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   XantPhos 4,5-bis(diphenylphosphino)-9.9-dimethylxanthene-   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Preparation of the Starting Compounds Intermediate 1a1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride

This compound and its precursors were synthesised as described inInternational application PCT/US2004/020209.

ESI-MS: m/z=219 (M+H)⁺

R_(f): 0.11 (silica gel, DCM/MeOH/NH₄OH=80:20:2)

Intermediate 1b 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one

Step 1: benzyl 4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate

560 mL (7.25 mol) TFA were added dropwise at approx. 15° C. to 930 g(3.99 mol) N-benzyloxy carbonyl-4-piperidone and 466 g (3.63 mol)2-chloro-3-aminopyridine in 9.5 L isopropyl acetate. 922 g (4.35 mol)sodium triacetoxyborohydride were added batchwise. The mixture wasstirred until the reaction was complete. At RT the reaction mixture wascombined with 860 mL sodium hydroxide solution (2 mol/L). The organicphase was separated off, washed with 5 L water and evaporated down.

Yield: 1250 g (crude, quant.)

ESI-MS: m/z=346 (M+H)⁺

Step 2: benzyl4-[1-(2-chloro-pyridin-3-yl)-ureido]-piperidine-1-carboxylate

530 mL (6.1 mol) chlorosulphonyl isocyanate were placed in 6 L THF andcooled to −15° C. Then a solution of 1.25 kg (3.63 mol) benzyl4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate in 7 L THF wasadded dropwise to this mixture within one hour such that the temperatureof the reaction mixture did not exceed −7° C. The mixture was stirredfor a further 90 minutes at approx. −8° C. and then 700 mL water wasadded dropwise within 30 minutes. The mixture was stirred for another 30minutes at approx. 10° C. and then slowly combined with 8.1 L sodiumhydroxide solution (2 mol/L). The reaction mixture was then heated to50° C. and the phases were separated. The organic phase was washed with2 L water. Then 10 L solvent were distilled off from the organic phase,15 L butyl acetate were added to the residue and another 8 L weredistilled off. By slow cooling to 0° C. the product was crystallised.The precipitate was suction filtered, washed with 2 L butyl acetate anddried at 40° C.

Yield: 1108 g (79% of theory)

ESI-MS: m/z=389/391 (M+H)⁺

Step 3: benzyl4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidine-1-carboxylate

1108 g (2.85 mol) benzyl4-[1-(2-chloro-pyridin-3-yl)-ureido]-piperidine-1-carboxylate wererefluxed with 720 g (8.57 mol) sodium hydrogen carbonate in 14.5 Ltert-amylalcohol. 3 L of solvent were distilled off. The reactionmixture was cooled to 35° C. and mixed with 11 mL water. Then 13 g(0.058 mol) palladium acetate and 49 g (0.115 mol)1,4-bis-(diphenylphosphino)-butane (DPPB) were added and the mixture wasrefluxed. It was stirred at 100° C. until the reaction was complete,cooled to RT and 7.5 L water were added. The organic phase was separatedoff, washed with 5 L water and then evaporated down. The oily residuewas twice combined with 3 L isopropyl acetate and distilled off. Thenthe residue was dissolved hot in 7 L isopropyl acetate and slowly cooledto ambient temperature. The solid that crystallised out was suctionfiltered, washed with 2 L isopropyl acetate and tert.-butyl-methyletherand dried at 50° C.

Yield: 690 g (69% of theory)

ESI-MS: m/z=353 (M+H)⁺

Step 4: 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

690 g (1.96 mol) benzyl4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl-piperidine-1-carboxylatewere dissolved in 5.4 L methanol and hydrogenated with the addition of46 g Pd/C (10%; 6.6% by weight) at 60° C. and a hydrogen pressure of 60psi until the uptake of hydrogen was complete. The catalyst was filteredoff. 4 L methanol were distilled off from the filtrate. 2 Lmethylcyclohexane were added and a further 1.5 L solvent were distilledoff. The suspension thus obtained was suction filtered, the residue waswashed with methylcyclohexane and dried at 40° C.

Yield: 446 g (100% of theory)

ESI-MS: m/z=219 (M+H)⁺

Intermediate 23-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

This compound and its precursors were synthesised as described inEuropean Patent Application No. EP 1 619 187.

ESI-MS: m/z=246 (M+H)⁺

Intermediate 37-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

801 mg (6.0 mmol) N-chlorosuccinimide were added to 1.23 g (5.0 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 10 mLcarbon tetrachloride and the reaction mixture was refluxed for 3 days.The solvent was evaporated down using the rotary evaporator and theresidue was purified by flash chromatography. The product fractions werecombined and the solvent was eliminated using the rotary evaporator. Forfurther purification the product fractions were purified by preparativeHPLC. The product fractions were combined and evaporated to drynessusing the rotary evaporator.

Yield: 420 mg (30% of theory)

ESI-MS: m/z=280/282 (M+H)⁺

R_(t) (HPLC-MS): 2.04 min (method E)

Intermediate 47-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

Step 1:(5-methoxy-2-nitrophenyl)-acetonitrile

24.0 g (214 mmol) potassium-tert-butoxide in 100 mL DMF were slowlyadded dropwise to a solution of 13.2 g (86.0 mmol) 4-nitroanisole and18.0 g (107 mmol) 4-chlorophenoxyacetonitrile in 50 mL DMF. The reactionmixture was stirred for 30 min at −10° C. and then poured into 300 g ofa 1:1 mixture of conc. hydrochloric acid and ice. After extraction withEtOAc the organic phase was washed with water, dried and evaporated todryness by rotary evaporation in vacuo with gentle heating. The residuewas treated with a 1:1 mixture of petroleum ether/EtOAc and the productthat crystallised out was suction filtered. After washing with a 1:1mixture petroleum ether/EtOAc the crystals were dried in the air.

Yield: 6.5 g (39% of theoretical)

ESI-MS: m/z=210 (M+NH₄)⁺

R_(f): 0.45 (silica gel; PE/EtOAc=1:1)

Step 2: 2-(5-methoxy-2-nitrophenyl)-ethylamine

Under a nitrogen atmosphere 200 mL (200 mmol) of a 1M borane in THFsolution were slowly added dropwise at RT to 12.6 g (65.7 mmol)(5-methoxy-2-nitrophenyl)-acetonitrile in 380 mL THF. The reactionmixture was refluxed for 2 h. After cooling 30 mL methanol were addeddropwise within 20 min. During this time the temperature was maintainedat 10° C. to 20° C. with an ice bath. The reaction mixture was stirredfor 30 min at RT and then 45 mL of a 2M aqueous hydrochloric acidsolution was added dropwise thereto within 30 min. The reaction mixturewas concentrated by rotary evaporation i. vac. with gentle heating. Theresidue was diluted with water to approx. 200 mL and extracted with 200mL EtOAc. The aqueous phase was made alkaline with a 15% (w/v) aqueouspotassium carbonate solution and continuously extracted overnight with arotary perforator according to Ludwig (Messrs. Normag) with diethylether. The organic extract was evaporated to dryness by rotaryevaporation.

Yield: 9.98 g (77% of theoretical)

ESI-MS: m/z=197 (M+H)⁺

R_(t)(HPLC): 2.1 min (method E)

Step3:(1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine

Under a nitrogen atmosphere a mixture of 9.98 g (50.9 mmol)2-(5-methoxy-2-nitrophenyl)-ethylamine, 9.8 mL (54.9 mmol)N-benzylpiperidone and 6.3 mL (114 mmol) acetic acid in 270 mLdichloromethane was cooled to 0° C. in an ice bath. At this temperature14.2 g (67.0 mmol) sodium triacetoxyborohydride were added batchwisewithin 20 min. The reaction mixture was left for a further 4 h at 0° C.with stirring and heated to RT overnight. Then the mixture was combinedwith 400 mL of a 15% (w/v) aqueous potassium carbonate solution andstirred for 1 h at RT. The organic phase was separated off, dried andconcentrated by rotary evaporation.

Yield: 18.8 g (quantitative)

ESI-MS: m/z=370 (M+H)⁺

R_(t)(HPLC): 1.9 min (method E)

Step 4:[2-(2-amino-5-methoxy-phenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine

26.0 g (70.3 mmol)(1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine werehydrogenated with 5.0 g (2.45 mmol) rhodium charcoal (5%, moistened withwater) in 350 mL methanol in a 3 bar hydrogen atmosphere for 3 h at RT.The catalyst was removed by suction filtering and the solutionconcentrated by rotary evaporation. The residue was immediately reactedfurther without any further purification.

Yield: 23.9 g (quantitative)

R_(t)(HPLC): R_(t)=0.99 min (method A)

Step 5:3-(1-benzylpiperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

35.0 g (216 mmol) N,N′-carbonyldiimidazole were added to 23.9 g (70.3mmol) [2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-aminein 175 mL DMF and the mixture was stirred for 2 h at 100° C. Thereaction mixture was poured onto approx. 1 kg ice water and stirredovernight. The precipitated product was suction filtered, washed with100 mL water and dried. The residue was stirred with 150 mL DIPE andsuction filtered. The solid product was washed with 50 mL DIPE anddried.

Yield: 21.6 g (84% of theoretical)

ESI-MS: m/z=366 (M+H)⁺

R_(t)(HPLC): 2.12 min (method E)

Step 6:7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

A mixture of 21.6 g (59.2 mmol)3-(1-benzylpiperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 2.5 g palladium on charcoal (10%) in 300 mL methanol washydrogenated in a 3 bar hydrogen atmosphere at 50° C. until the reactionwas complete. The catalyst was removed by suction filtering and themother liquor concentrated by rotary evaporation. The residue wastriturated with 150 mL DIPE, suction filtered, washed with 100 mL DIPEand dried.

Yield: 13.2 g (81% of theoretical)

ESI-MS: m/z=276 (M+H)⁺

R_(t)(HPLC): 0.73 min (method L)

Intermediate 5 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

Step 1: 3-bromoquinoline-1-oxide

A solution of 72% 3-chloroperbenzoic acid (97.8 g (0.408 mol) dissolvedin 1 L DCM, dried on sodium sulphate and filtered off) was addeddropwise to a solution of 85.0 g 0.41 mol) 3-bromoquinoline in 100 mLDCM cooled to 5° C. Care was taken to ensure that the temperature of thereaction mixture did not rise above 10° C. After the addition had endedthe mixture was stirred for 5 h, then a solution of 72%3-chloroperbenzoic acid (25.0 g, 0.104 mol) dissolved in 200 mL DCM,dried on sodium sulphate and filtered off) was again added dropwise andthe mixture was stirred overnight at RT. Saturated aqueous sodiumcarbonate solution was added, the phases were separated and the organicphase was dried on sodium sulphate. The solution was filtered throughactivated charcoal and then evaporated down i. vac.

Yield: 91 g (99% of theoretical)

MS: m/z=223/225 (M)⁺

R_(f): 0.15 (silica gel, eluant B)

Step 2: 3-bromo-4-nitroquinoline-1-oxide

A solution of 190 g (0.85 mol) 3-bromoquinoline-1-oxide in 500 mLconcentrated sulphuric acid was heated to 90° C. Then 120 g (1.19 mol)potassium nitrate were added in small batches over a period of 100 minsuch that the temperature of the reaction did not rise above 95° C. Themixture was stirred for 3 h at 90° C.; it was left to cool to RT and themixture was poured onto ice. The precipitated product was filtered offand the filter cake washed with water. The residue was dissolved in DCMand washed with saturated aqueous sodium hydrogen carbonate solution,until the solution reacted in alkaline manner. The phases were separatedand the aqueous phase was again extracted with DCM. The combined organicphases were dried on sodium sulphate and evaporated down i. vac. Aftercomminution of the residue and exhaustive drying i. vac. the product wasobtained.

Yield: 104 g (46% of theoretical)

MS: m/z=268/270 (M)⁺

R_(f): 0.77 (silica gel, EtOAc)

Step 3:(1-benzylpiperidin-4-yl)-(4-nitro-1-oxyquinolin-3-yl)-amine

104 g (0.387 mol) 3-bromo-4-nitroquinoline-1-oxide were added to 320 mL(1.54 mol) 4-amino-1-benzylpiperidine. Then 500 mL THF were added andthe mixture was hated until the substances were fully dissolved. Then itwas stirred for 3 h at 70° C. and the reaction mixture was thenevaporated down i. vac. The residue obtained was dissolved in 2.5 L DCMand washed with saturated aqueous sodium hydrogen carbonate solution.The aqueous phase was again extracted with 300 mL DCM. Then the organicphases were combined, dried on sodium sulphate and evaporated down i.vac. The residue was dissolved in 250 mL methanol. The productprecipitated as a solid was suction filtered and dried i. vac.

Yield: 104 g (71% of theoretical)

ESI-MS: m/z=379 (M+H)⁺

R_(f): 0.75 (silica gel, EtOAc)

Step 4: N³-(1-benzylpiperidin-4-yl)quinoline-3,4-diamine

12.0 g rhodium charcoal (5%, moistened with water) were added to asolution of 76.0 g (0.20 mol)(1-benzylpiperidin-4-yl)-(4-nitro-1-oxyquinolin-3-yl)-amine in 1.0 LTHF. The reaction was shaken for 4.5 h under a hydrogen atmosphere (50psi) at RT. The catalyst was filtered off and the solvent was eliminatedi. vac. Because of its proneness to oxidation the crude product was usedimmediately for the next step.

Yield: 66.0 g (99% of th.)

R_(f): 0.30 (silica gel, eluant A)

Step 5:3-(1-benzylpiperidin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one

22.6 g (139 mmol) 1,1′-carbonyldiimidazole were added to a solution of9.0 g (27.1 mmol) N³-(1-benzylpiperidin-4-yl)-quinoline-3,4-diamine in100 mL DMF. The mixture was heated to 100° C. and stirred for 1.5 h atthis temperature. After cooling the reaction mixture it was poured onto300 mL water. The precipitated solid was filtered off, washed with waterand dried at 30° C. i. vac. The residue was triturated with diethylether, suction filtered and the solid product was dried i. vac.

Yield: 7.42 g (77% of theoretical)

ESI-MS: m/z=359 (M+H)⁺

R_(t)(HPLC): 1.6 min (method E)

Step 6: 3-piperidin-4-yl-1,3-dihydroimidazo[4,5-c]quinolin-2-one

A mixture of 44.0 g (0.123 mol)3-(1-benzylpiperidin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one and10.0 g palladium (Pd/C 10%) in 500 mL methanol was hydrogenated for 16 hat 50 C in a hydrogen atmosphere of 50 psi. After filtration of thereaction mixture the solvent was eliminated in vacuo. The product wasprecipitated out by the addition of isopropanol. It was filtered off anddried.

Yield: 31.2 g (95% of theoretical)

ESI-MS: m/z=269 (M+H)⁺

R_(f): 0.20 (silica gel, eluant A)

Intermediate 6 6-chloropyrimidine-4-carboxylic acid chloride

Step 1: 6-hydroxypyrimidine-4-carboxylic acid

63.5 g (0.29 mol) sodium diethyloxalacetate and 30.2 g (0.29 mol)formamidine acetate were added to 24.1 g (0.6 mol) NaOH in 3.6 L water.The mixture was stirred overnight at RT. Then activated charcoal wasadded and the mixture was refluxed for 1 h. It was filtered off hot andafter cooling acidified with aqueous hydrochloric acid. The solution wasevaporated to dryness by rotary evaporation. The residue contained thedesired product and was used in the next step without any furtherpurification.

Yield: 83.0 g

Step 2: 6-chloropyrimidine-4-carboxylic acid chloride

50.0 g (0.35 mol) 6-hydroxypyrimidine-4-carboxylic acid was taken and500 mL phosphorus oxychloride were added. Then 150 g (0.720 mol)phosphorus pentachloride was added batchwise with stirring. The reactionmixture was refluxed for 5 h. The phosphorus oxychloride was distilledoff and the residue was purified by vacuum distillation through acolumn.

Yield: 51.9 g (83% of theoretical)

MS: m/z=176/178/180 (M)⁺

Intermediate 7 ethyl 6-chloropyrimidine-4-carboxylate

1.0 g (5.65 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 0.4mL (6.94 mmol) ethanol were combined in 30 mL dichloromethane andstirred overnight at RT. The solvent was eliminated i.vac.

Yield: 1.0 g (95% of theoretical)

ESI-MS: m/z=187/189 (M+H)⁺

R_(f): 0.85 (silica gel, EtOAc)

Intermediate 8 benzoate ethyl3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-

Under a nitrogen atmosphere 1.06 g (4.32 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 2.15 g(6.60 mmol) caesium carbonate, 100 mg (0.45 mmol) palladium-(II)-acetateand 280 mg (0.45 mmol) BINAP were stirred in 40 mL xylene for 10 min atRT. 850 μL (5.20 mmol) of ethyl 3-bromobenzoate were added and themixture was stirred overnight at 120° C. Then the insoluble solid wassuction filtered and the filtrate was evaporated down i. vac. Theresidue was purified by flash chromatography. The combined productfractions were evaporated down i. vac. The residue was stirred withdiisopropylether and suction filtered. The solid was dried at 50° C. inthe CAD.

Yield: 650 mg (38% of theoretical)

ESI-MS: m/z=394 (M+H)⁺

R_(f): 0.81 (silica gel, eluant A)

Intermediate 93-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoicacid

650 mg (1.65 mmol) ethyl3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoate,10 mL THF, 2 mL water and 2 mL (8.00 mmol) of an aqueous 4M sodiumhydroxide solution were stirred at RT until the reaction was complete.Then the THF was eliminated i. vac. The aqueous residue was acidifiedwith a 4M hydrochloric acid solution. After several hours' stirring atRT the precipitate was suction filtered and dried.

Yield: 540 mg (90% of theoretical)

ESI-MS: m/z=366 (M+H)⁺

R_(f): 0.20 (silica gel, eluant A)

Intermediate 10 ethyl6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate

700 mg (2.85 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 470 μL(2.73 mmol) DIPEA were added to 500 mg (2.68 mmol) ethyl6-chloropyrimidine-4-carboxylate in 10 mL DMF and the reaction mixturewas stirred for 1 h at RT. The reaction mixture was diluted with waterand stirred for 30 min. The precipitate was suction filtered, washedwith water and dried at 50° C. in the CAD.

Yield: 620 mg (59% of theoretical)

ESI-MS: m/z=396 (M+H)⁺

R_(f): 0.48 (silica gel, eluant A)

Intermediate 116-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid

590 mg (1.49 mmol) ethyl6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate,20 mL ethanol, 1 mL water and 1 mL (4.0 mmol) of a 4M NaOH solution werestirred for 2 h at RT. The reaction mixture was diluted with water untilthe precipitate had dissolved. 1 mL of a 4M hydrochloric acid solutionwere added and the ethanol was eliminated i. vac. The reaction mixturewas stirred for 30 min at RT, the precipitate was suction filtered anddried at 50° C. in the CAD.

Yield: 500 mg (91% of theoretical)

MS: m/z=367 (M)⁺

R_(f): 0.13 (silica gel, eluant A)

Intermediate 12 ethyl6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate

2.80 g (10.2 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 6.00 mL (34.9 mmol) DIPEA were added to 1.90 g (10.2 mmol) ethyl6-chloropyrimidine-4-carboxylate in 60 mL DMF and the reaction mixturewas stirred for 3 h at RT. After elimination of the solvent i. vac. theresidue was combined with 70 mL water and stirred for 10 min. 5 mL ethylacetate were added. After vigorous stirring the solid was suctionfiltered and dried in the CAD.

Yield: 2.55 g (59% of theoretical)

ESI-MS: m/z=426 (M+H)⁺

R_(f): 0.63 (silica gel, eluant A)

Intermediate 136-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-O-piperidin-1-yl]-pyrimidine-4-carboxylicacid

2.55 g (5.99 mmol) ethyl6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate,50 mL THF and 5 mL (20.0 mmol) of a 4M NaOH solution were stirredovernight at RT. After elimination of THF i. vac. The aqueous residuewas combined with 5 mL of a 4 M hydrochloric acid solution. Thesupernatant solution was decanted off, the oily residue was again mixedwith 50 mL water and stirred overnight at RT. The precipitate wassuction filtered and dried at 50° C. in the CAD.

Yield: 2.05 g (86% of theoretical)

MS: m/z=397 (M)⁺

R_(f): 0.23 (silica gel, eluant A)

Intermediate 14 ethyl6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate

5.40 g (18.6 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochlorideand 11 mL (63.93 mmol) DIPEA were added to 3.40 g (18.2 mmol) ethyl6-chloropyrimidine-4-carboxylate in 80 mL DMF. After 3 h stirring at RTthe solvent was eliminated i.vac. The residue was combined with 70 mLwater and stirred for 10 min. 5 mL ethyl acetate were added and themixture was stirred vigorously. The precipitated solid was suctionfiltered and dried at 40° C. in the circulating air dryer.

Yield: 5.50 g (82% of theoretical)

ESI-MS: m/z=369 (M+H)⁺

R_(f): 0.48 (silica gel; eluant A)

Intermediate 156-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid

9.0 mL (36.0 mmol) of a 4M NaOH solution were added to 5.50 g (14.9mmol) ethyl6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate,25 mL water in 150 mL THF. After 3 h stirring at RT the THF waseliminated i. vac. The aqueous residue was combined with 9 mL of a 4Mhydrochloric acid solution. After 3 h stirring at RT the precipitate wassuction filtered and dried in the CAD at 60 C.

Yield: 4.5 g (89% of theoretical)

ESI-MS: m/z=341 (M+H)⁺

R_(f): 0.07 (silica gel; eluant A)

Intermediate 16 (2-chloropyridin-4-yl)-(2,3-dihydroindol-1-yl)-methanone

400 μL (3.53 mmol) 2,3-dihydro-1H-indole were added to 500 mg (3.17mmol) 2-chloroisonicotinic acid, 600 μL (3.49 mmol) DIPEA and 1.10 g(3.43 mmol) TBTU in 20 mL THF. The reaction mixture was stirredovernight, diluted with ethyl acetate and washed with 15% potassiumcarbonate solution (1×), water (1×) and 1M hydrochloric acid (1×). Theorganic phase was dried on magnesium sulphate, filtered and evaporateddown i. vac. The residue was triturated with diisopropylether andsuction filtered. The solid was dried at 40° C. in the circulating airdryer.

Yield: 700 mg (85% of theory)

ESI-MS: 259/261 (M+H)⁺

R_(f): 0.38 (silica gel, eluant B)

Intermediate 17(2-chloropyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone

174 mg (1.27 mmol) 5-fluoro-2,3-dihydro-1H-indole were added to 198 mg(1.26 mmol) 2-chloroisonicotinic acid, 351 μL (2.50 mmol) triethylamineand 434 mg (1.35 mmol) TBTU in 3 mL DMF. The reaction mixture wasstirred overnight at RT. Purification was carried out by preparativeHPLC. The product fractions were combined and evaporated down i. vac.

Yield: 230 mg (66% of theory)

ESI-MS: 277/279 (M+H)⁺

R_(t) (HPLC-MS): 4.0 min (method E)

Intermediate 18 (4-chloropyridin-2-yl)-(2,3-dihydroindol-1-yl)-methanone

800 μL (7.07 mmol) 2,3-dihydro-1H-indole were added to 1.0 g (6.35 mmol)4-chloropyridine-2-carboxylic acid, 1.0 mL (7.12 mmol) triethylamine and2.20 g (6.85 mmol) TBTU in 100 mL THF. The reaction mixture was stirredfor 3 h at RT, diluted with ethyl acetate (100 mL) and washed with 15%potassium carbonate solution (2×50 mL), saturated sodium chloridesolution (1×50 mL) and 1M hydrochloric acid (2×30 mL). The organic phasewas dried on magnesium sulphate, filtered and evaporated down i. vac.

Yield: 850 mg (52% of theory)

ESI-MS: 259/261 (M+H)⁺

R_(f): 0.88 (silica gel, EtOAc)

Intermediate 19(4-chloropyridin-2-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone

174 mg (1.27 mmol) 5-fluoro-2,3-dihydro-1H-indole were added to 200.0 mg(1.27 mmol) 4-chloropyridine-2-carboxylic acid, 351 μL (2.50 mmol)triethylamine and 434.0 mg (1.35 mmol) TBTU in 3 mL DMF. The reactionmixture was stirred overnight at RT. Purification was carried out bypreparative HPLC. The product fractions were combined and evaporateddown i. vac.

Yield: 300 mg (85% of theory)

ESI-MS: 277/279 (M+H)⁺

R_(t) (HPLC-MS): 4.1 min (method E)

Intermediate 20 (6-chloropyrimidin-4-yl)-(octahydroindol-1-yl)-methanone

0.517 g (2.92 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 10mL dichloromethane were combined with 1.07 mL (6.00 mmol) DIPEA. 0.73 g(2.92 mmol) octahydroindole in 10 mL DCM was slowly added dropwise.After 2 h stirring at RT the mixture was diluted with dichloromethaneand extracted with water. The organic phase was separated off, dried onsodium sulphate, filtered, evaporated down i. vac. and dried.

The product thus obtained was reacted without further purification.

Yield: 800 mg (quant.)

ESI-MS: 266/268 (M+H)⁺

R_(t) (HPLC-MS): 3.62 min (method E)

Intermediate 21(6-chloropyrimidin-4-yl)-(2,3-dihydroindol-1-yl)-methanone

500 mg (2.83 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20mL dichloromethane were cooled with a bath of ice/ethanol and mixed with0.300 mL (2.68 mmol) 2,3-dihydro-1H-indole. 2.70 mL (2.70 mmol) of a 1Msodium hydroxide solution were added dropwise. The reaction mixture wasstirred for 2 h while being cooled and for 1 h at RT. Then 50 mL of anaqueous saturated sodium hydrogen carbonate solution were added. After10 min stirring the organic phase was separated off and extracted withwater (1×30 mL) and with 1 M hydrochloric acid (1×50 mL). The organicphase was dried on magnesium sulphate, filtered and evaporated down i.vac.

Yield: 570 mg (78% of theoretical)

ESI-MS: m/z=260/262 (M+H)⁺

R_(f): 0.59 (silica gel, eluant B)

General method of reacting 6-chloropyrimidine-4-carboxylic acid chloridewith heterocycles containing nitrogen:

1.50 g (8.48 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 50mL dichloromethane were cooled with a bath of ice/ethanol and combinedwith the amount of a nitrogen-containing heterocyclic group specified ineach case. 7.90 mL (7.90 mmol) of a 1M sodium hydroxide solution wereadded dropwise. The reaction mixture was stirred for 2 h while beingcooled and for 1 h at RT. Then 50 mL of a saturated sodium hydrogencarbonate solution were added. After 10 min stirring the organic phasewas separated off and extracted with water (1×30 mL) and then with 1 Mhydrochloric acid (1×50 mL). The organic phase was dried on magnesiumsulphate, filtered and evaporated down i. vac. The product was reactedwithout further purification.

N heterocycle [amount of N Analytical Intermediate Structureheterocycle] Yield data 22

2,3-dihydro-1H- isoindole 0.89 mL (7.84 mmol) 1.8 g (82% of theory)ESI-MS: m/z = 260/262 (M + H)⁺ R_(f) = 0.57 eluant B(6-chloropyrimidin-4-yl)-(1,3- dihydroisoindol-2-yl)-methanone 23

1,2,3,4-tetrahydro- isoquinoline 0.978 mL (7.81 mmol) 1.7 g (73% oftheory) ESI-MS: m/z = 274/276 (M + H)⁺ R_(f) = 0.46 eluant B(6-chloropyrimidin-4-yl)-(3,4- dihydro-1H-isoquinolin-2-yl)-methanone 24

2,3,4,5-tetrahydro- 1H-1-benzazepine 1.15 g (7.81 mmol) 2.0 g (82% oftheory) ESI-MS: m/z = 288/290 (M + H)⁺ R_(f) = 0.61 eluant A(6-chloropyrimidin-4-yl)-(3,4- dihydro-2H-quinolin-1-yl)-methanone

Intermediate 25(5-chloro-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone

1.50 g (8.48 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 50mL dichloromethane were cooled with a bath of ice/ethanol and combinedwith 1.20 g (7.81 mmol) 5-chloro-2,3-dihydro-1H-indole. 7.90 mL (7.90mmol) of a 1M sodium hydroxide solution were added dropwise. Thereaction mixture was stirred for 2 h while being cooled and for 1 h atRT. Then 50 mL of an aqueous saturated sodium hydrogen carbonatesolution were added. After 10 min stirring the organic phase wasseparated off and extracted with water (1×30 mL) and with 1 Mhydrochloric acid (1×50 mL). The organic phase was dried on magnesiumsulphate, filtered and evaporated down i. vac.

Yield: 2.00 g (80% of theoretical)

ESI-MS: m/z=294/296/298 (M+H)⁺

R_(f): 0.65 (silica gel, eluant B)

Intermediate 26(5-bromo-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone

2.0 g (11.3 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 50 mLdichloromethane were cooled with a bath of ice/ethanol and combined with2.2 g (10.9 mmol) 5-bromo-2,3-dihydro-1H-indole. 10.9 mL (10.9 mmol) ofa 1M sodium hydroxide solution were added dropwise. The reaction mixturewas stirred for 2 h while being cooled. After the mixture had warmed upto RT, 50 mL of a saturated aqueous sodium hydrogen carbonate solutionwas added. The organic phase was separated off and extracted with water(1×) and with 1 M hydrochloric acid (1×). The organic phase was dried onmagnesium sulphate, filtered and evaporated down i. vac. The residue wastriturated with diisopropylether, suction filtered and dried at 50° C.in the CAD.

Yield: 620 mg (16% of theoretical)

MS: m/z=337/339/341 (M)⁺

R_(f): 0.89 (silica gel, EtOAc)

Intermediate 27 methyl (5-fluoro-2,3-dihydro-1H-indol-3-yl)-acetate

Step 1: methyl (5-fluoro-1H-indol-3-yl)-acetate

1.0 g (5.2 mmol) 5-fluoroindole-3-acetic acid was stirred in 60 mLmethanolic HCl at RT for 2 h. The solvent was eliminated using therotary evaporator. The product was reacted without further purification.

Yield: 1.0 g (93% of theory)

ESI-MS: m/z=208 (M+H)⁺

R_(t) (HPLC): 3.18 min (method E)

Step 2: methyl (5-fluoro-2,3-dihydro-1H-indol-3-yl)-acetate

Under a nitrogen atmosphere 910 mg (14.5 mmol) sodium cyanoborohydridewas added batchwise to 1.0 g (4.83 mmol) methyl(5-fluoro-1H-indol-3-yl)-acetate in 12.5 g acetic acid while coolingslightly. After 2 h stirring at RT another 910 mg (14.5 mmol) sodiumcyanoborohydride was added batchwise while cooling slightly. After 3 hstirring at RT the solvent was evaporated down using the rotaryevaporator. The residue was taken up in 4M hydrochloric acid and stirredfor 30 min. Then the reaction solution was made alkaline with solidpotassium carbonate and extracted with dichloromethane (3×). Thecombined organic phases were dried on sodium sulphate, filtered andevaporated down using the rotary evaporator. The product thus obtainedwas reacted directly.

Yield: 300 mg (30% of theory)

ESI-MS: m/z=210 (M+H)⁺

Intermediate 28 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole

Step 1: 1-acetyl-5-fluoro-1,3-dihydro-indol-2-one

At 170° C. 3.0 g (20 mmol) 5-fluoroindolinone were stirred for 3 h in 10mL (98 mmol) acetic anhydride. After cooling to RT the mixture waspoured onto 200 mL ice water, the precipitated substance was suctionfiltered and washed with 100 mL water. The solid was recrystallised from100 mL water and 50 mL ethanol at boiling temperature. The precipitatedproduct was suction filtered, washed with 30 mL water and dried in theCAD.

Yield: 2.4 g (63% of theory)

ESI-MS: m/z=192 (M+H)⁺

R_(t) (HPLC): 1.2 min (method C)

Step 2: 1-acetyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one

At 0° C. to 5° C., 1.14 g (26.0 mmol) 55% sodium hydride in oil wasadded batchwise under an argon atmosphere to 2.40 g (12.4 mmol)1-acetyl-5-fluoro-1,3-dihydroindol-2-one in 30 mL DMF and stirred for 1h. Then 1.91 mL (31.0 mmol) methyl iodide were added dropwise and themixture was stirred overnight at RT. The reaction mixture was pouredonto 200 mL water and the precipitated substance was suction filtered.The solid was washed with 50 mL water and dried in the CAD.

Yield: 2.1 g (76% of theory)

ESI-MS: m/z=222 (M+H)⁺

R_(t) (HPLC): 1.48 min (method C)

Step 3: 5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one

2.10 g (9.49 mmol)1-acetyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one in 20 mLisopropanol were refluxed with 50 mL of an aqueous 6N hydrochloric acidsolution for 1 h. After cooling the isopropanol was eliminated i. vac.The residue was diluted with 100 mL water and cooled with ice. Theprecipitated substance was suction filtered and washed with 30 mL water.The solid was dried in the CAD.

Yield: 1.40 g (82% of theory)

ESI-MS: m/z=180 (M+H)⁺

R_(t) (HPLC): 1.14 min (method C)

Step 4: 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole

Under an argon atmosphere a solution of 9.30 mL (9.30 mmol) of a 1Msolution lithium aluminium hydride in THF and 10 mL THF was slowly addeddropwise to 1.40 g (7.81 mmol)5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one in 50 mL THF. Then thereaction mixture was heated to 70° C. for 1 h. After cooling 2 mL waterwere added. The solution was dried on sodium sulphate and filtered off.The solvent was eliminated i. vac.

Yield: 1.30 g (quant)

ESI-MS: m/z=166 (M+H)⁺

R_(t) (HPLC): 0.75 min (method C)

Intermediate 29 3,3-dimethyl-2,3-dihydro-1H-indole

Step 1: 1-acetyl-1,3-dihydroindol-2-one

The compound was synthesised as in US Patent Application 2003/0069299.

Step 2: 1-acetyl-3,3-dimethyl-1,3-dihydroindol-2-one

At 0° C. to 5° C. 2.75 g (63.0 mmol) 55% sodium hydride in oil was addedbatchwise under an argon atmosphere to 5.30 g (30.0 mmol)1-acetyl-1,3-dihydroindol-2-one in 50 mL DMF and stirred for 1 h. Then4.70 mL (75 mmol) methyl iodide were added dropwise and the mixture wasstirred overnight at RT. The reaction mixture was poured onto water andextracted several times with tert-butylmethylether. The combined organicphases were dried and evaporated down i. vac. The residue was purifiedon a silica gel column. The product fractions were combined andevaporated to dryness by rotary evaporation.

Yield: 3.60 g (59% of theory)

ESI-MS: m/z=204 (M+H)⁺

R_(f): 0.9 ((silica gel, petroleum ether/dichloromethane/ethylacetate=5/4/1)

Step 3: 3,3-dimethyl-1,3-dihydroindol-2-one

3.50 g (17.2 mmol) 1-acetyl-3,3-dimethyl-1,3-dihydro-indol-2-one wererefluxed in 50 mL of a 6N hydrochloric acid solution for 1 h. Aftercooling the reaction mixture was divided between tert-butylmethyletherand water. The organic phase was washed with water, dried and evaporateddown. The residue was crystallised from PE. The solid was suctionfiltered and dried at 80° C. in the CAD.

Yield: 2.40 g (87% of theory)

ESI-MS: m/z=162 (M+H)⁺

R_(f) 0.3 (silica gel, petroleum ether/dichloromethane/ethylacetate=5/4/1)

Step 4: 3,3-dimethyl-2,3-dihydro-1H-indole

Under a nitrogen atmosphere a solution of 6.20 mL (6.20 mmol) of a 1Msolution lithium aluminium hydride in THF and 10 mL THF was slowly addeddropwise to 1.00 g (6.20 mmol) 3,3-dimethyl-1,3-dihydro-indol-2-one in50 mL THF. Then the reaction mixture was heated to 60° C. for 1 h. Aftercooling to 0° C., 3 mL ice water were slowly added dropwise. 20 g sodiumsulphate were added and the mixture was suction filtered. The solutionwas evaporated down i. vac.

Yield: 0.80 g (88% of theory)

ESI-MS: m/z=148 (M+H)⁺

R_(t) (HPLC): 0.7 min (method C)

Intermediate 30 Spiro[cyclobutan-1.3′-indoline]

Step 1:Cyclobutanecarboxylic acid N′-phenylhydrazide

3.54 mL (31.0 mmol) cyclobutanecarboxylic acid chloride were addeddropwise at RT to 3.00 mL (30.2 mmol) phenylhydrazine and 4.75 mL (60.0mmol) pyridine in 30 mL DMF. The mixture was stirred for 1 h at RT andpoured onto 200 mL of a 1M hydrochloric acid solution. The precipitatedsolid was suction filtered, washed with 50 mL water and dried i. vac.The product was extracted with 50 mL ether and suction filtered. Thesolid was washed with 20 mL ether and dried in the air.

Yield: 3.00 g (52% of theory)

ESI-MS: m/z=191 (M+H)⁺

R_(t) (HPLC-MS): 1.05 min (method C)

Step 2:spiro[cyclobutan-1,3′-indolin]-2′-one

Under a nitrogen atmosphere 1.50 g (7.89 mmol) cyclobutanecarboxylicacid N-phenylhydrazide and 530 mg (12.6 mmol) calcium hydride were mixedthoroughly and heated to 230° C. The mixture was stirred for 30 min at230° C. and then cooled to RT again. The reaction mixture was carefullymixed with a solution of 7 mL water and 16 mL methanol. It was stirredfor 1 h until no more hydrogen was released. Then the pH was adjusted to1 with concentrated hydrochloric acid solution and the mixture wasstirred for 1 h at 100° C. Using 4M sodium hydroxide solution the pH wasadjusted to 3 and stirred overnight at RT. The precipitated substancewas suction filtered and washed with 10 mL water. The mother liquor wasevaporated down i.vac. and the residue was purified by preparative HPLC.The product fractions were combined, evaporated down i.vac. and dried.

Yield: 100 mg (7% of theory)

ESI-MS: m/z=174 (M+H)⁺

R_(t) (HPLC-MS): 1.18 min (method C)

Step 3:spiro[cyclobutan-1,3′-indoline]

Under a nitrogen atmosphere 0.60 mL (0.60 mmol) of a 1M solution oflithium aluminium hydride in THF was added dropwise to 100 mg (0.58mmol) spiro[cyclobutan-1,3′-indolin]-2′-one in 20 mL THF. Then thereaction mixture was stirred for 1 h at 65° C. After cooling 1 mL waterwas added and the mixture was stirred for 10 min. The organic phase wasdried on sodium sulphate and evaporated down. The product was reactedwithout further purification.

Yield: 100 mg (quant)

ESI-MS: m/z=160 (M+H)⁺

R_(t) (HPLC-MS): 0.77 min (method C)

Intermediate 31 3-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-1H-indole

Step 1: 3-(1H-indol-3-yl)-1-pyrrolidin-1-yl-propan-1-one

681 mg (3.60 mmol) 3-(1H-indol-3-yl)-propionic acid, 0.3 mL (3.60 mmol)pyrrolidine, 1.13 g (3.50 mmol) TBTU and 0.98 mL (7.00 mmol)triethylamine in 5.0 mL DMF were stirred overnight at RT. The mixturewas purified by preparative HPLC. The product fractions were combinedand evaporated down i. vac.

Yield: 670 mg (77% of theory)

ESI-MS: m/z=243 (M+H)⁺

R_(t) (HPLC-MS): 3.33 min (method E)

Step 2: 3-(3-pyrrolidin-1-yl-propyl)-1H-indole

Under a nitrogen atmosphere 3.40 mL (3.40 mmol) of a 1M lithiumaluminium hydride solution in THF was slowly added dropwise to 670 mg(2.77 mmol) 3-(1H-indol-3-yl)-1-pyrrolidin-1-yl-propan-1-one in 30 mLTHF. The reaction mixture was stirred for 1 h at 65 C and after coolingcombined with 1 mL water. After 10 min stirring at RT the organic phasewas dried on sodium sulphate and evaporated down i. vac. The product wasreacted further without any further purification.

Yield: 600 mg (95% of theory)

ESI-MS: m/z=229 (M+H)⁺

R_(t) (HPLC-MS): 0.9 min (method C)

Step 3: 3-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-1H-indole

At 15° C. 508 mg (8.10 mmol) sodium cyanoborohydride was added to 600 mg(2.63 mmol) 3-(3-pyrrolidin-1-yl-propyl)-1H-indole in 7.50 g acetic acidand the mixture was stirred for 1 h at 15° C. After this time another600 mg sodium cyanoborohydride were added and the mixture was stirred at15° C. for 3 h. The reaction mixture was evaporated down using therotary evaporator and combined with 40 mL of a 4M hydrochloric acidsolution. The reaction mixture was stirred for 1 h at RT. Then themixture was made basic with potassium carbonate and extracted with ethylacetate (2×50 mL). The combined organic phases were dried and evaporateddown i. vac. The product was reacted further without any furtherpurification.

Yield: 600 mg (99% of theory)

ESI-MS: m/z=231 (M+H)⁺

R_(t) (HPLC-MS): 0.25 min (method C)

Intermediate 32 ethyl 2,3-dihydro-1H-indole-2-carboxylate hydrochloride

1.50 g (9.19 mmol) 2,3-dihydro-1H-indole-2-carboxylic acid in 50 mLethanolic hydrochloric acid were stirred overnight at RT. The solventwas eliminated using the rotary evaporator.

Yield: 2.10 g (quant)

ESI-MS: m/z=192 (M+H)⁺

Intermediate 337,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazol[4,3-c]pyridine-dihydrochloride

At 0° C. 5 mL trifluoroacetic acid was added to 1.60 g (6.05 mmol)tert-butyl7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate(synthesised analogously to WO2005/065779) in 15 mL dichloromethane andthe reaction mixture was stirred for 2 h at RT. Then the solvent waseliminated i. vac. The residue was combined with ethanol and evaporateddown again i. vac. The residue was dissolved in ethanol and 12 mL of a1.25 M ethanolic HCl solution were added. The mixture was againevaporated down i. vac. The residue was triturated with ethanol. Thesolid was suction filtered and dried.

Yield: 1.24 g (92% of theoretical)

ESI-MS: m/z=152 (M+H)⁺

R_(t) (HPLC): 0.65 min (method N)

Intermediate 34 1,1-dimethyl-2-m-tolyl-ethylamine

Step 1: ethyl m-tolyl-acetate

50 mL ethanolic hydrochloric acid were added to 25.5 g (169 mmol)m-tolylacetic acid in 200 mL ethanol and the mixture was stirredovernight at RT. After elimination of the solvent using the rotaryevaporator the residue was combined with 250 mL EtOAc and extracted with150 mL of a 15% potassium carbonate solution. The organic phase wasdried on magnesium sulphate, filtered and evaporated to dryness usingthe rotary evaporator.

Yield: 25.6 g (85% of theory)

MS: m/z=178 (M)⁺

R_(f): 0.76 (silica gel, PE/EtOAc=8/2)

Step 2: 2-methyl-1-m-tolylpropan-2-ol

At 10° C., 17.8 g (99.87 mmol) ethyl m-tolyl-acetate in 400 mL THF wasslowly added dropwise to 100 mL (300.0 mmol) of a 3M solution ofmethylmagnesium bromide in THF over an hour. The reaction mixture washeated for 30 min at RT and refluxed for 3 h. After cooling 250 mL of asaturated ammonium chloride solution were slowly added dropwise. Themixture was left to stand overnight. 300 mL of a 0.5 M hydrochloric acidsolution were added and it was briefly stirred. The phases wereseparated and the aqueous phase was extracted with EtOAc. The combinedorganic phases were washed with saturated sodium chloride solution,dried on magnesium sulphate, filtered and evaporated down i. vac.

Yield: 14.7 g (90% of theory)

R_(f): 0.39 (silica gel, PE/EtOAc=8/2)

Step 3: N-(1,1-dimethyl-2-m-tolylethyl)-formamide

While cooling with ice 5.20 g (106 mmol) sodium cyanide were added to 60mL glacial acetic acid. After brief stirring 40 mL conc. Sulphuric acidwas added dropwise at 0° C. such that the reaction temperature did notrise above 20° C. After brief stirring 14.5 g (88.3 mmol)2-methyl-1-m-tolylpropan-2-ol in 40 mL glacial acetic acid were addeddropwise at 0° C. such that the reaction temperature did not rise above20° C. The reaction mixture was stirred for 10 min at 0° C. andovernight at RT. The reaction mixture was poured onto ice andneutralised with 40% sodium hydroxide solution. The aqueous phase wasextracted with EtOAc (3×150 mL). The combined organic phases were washedwith 15% potassium carbonate solution, dried, filtered and evaporateddown i. vac.

Yield: 14.4 g (85% of theory)

ESI-MS: m/z=192 (M+H)⁺

R_(f): 0.31 (silica gel, PE/EtOAc=8/2)

Step 4: 1,1-dimethyl-2-m-tolylethylamine

1.80 g (9.41 mmol) N-(1,1-dimethyl-2-m-tolylethyl)-formamide, 20 mLwater and 20 mL conc. hydrochloric acid were refluxed for 2 h. Thereaction mixture was diluted with 20 mL ice water and made alkaline withsaturated potassium carbonate solution. The aqueous phase was extractedwith DCM (2×20 mL). The organic phase was washed with water, dried onsodium sulphate and evaporated down i. vac. The residue wasco-evaporated with toluene (2×).

Yield: 1.30 g (85% of theory)

ESI-MS: m/z=164 (M+H)⁺

Intermediate 35 3,3-dimethylpyrrolidine hydrochloride

Step 1: 1-benzyl-3,3-dimethylpyrrolidin-2,5-dione

25.0 g (171 mmol) 2,2-dimethylsuccinic acid and 20.6 mL (188 mmol)benzylamine were refluxed for 1.5 h with stirring in an apparatus withwater separator. The xylene was evaporated off by rotary evaporation andthe residue was divided between 300 mL EtOAc and 150 mL of a 5% sodiumhydrogen carbonate solution. The organic phase was dried on sodiumsulphate, suction filtered and concentrated by rotary evaporation. Theresidue was crystallised from isopropanol in a bath of dry ice.

Yield: 34.6 g (93% of theory)

ESI-MS: m/z=218 (M+H)⁺

R_(f) 0.58 (silica gel, PE/EtOAc=4/1)

Step 2: 1-benzyl-3,3-dimethylpyrrolidine

34.5 g (158.8 mmol) 1-benzyl-3,3-dimethyl-pyrrolidin-2,5-dione in 200 mLTHF was slowly added dropwise at 10° C. to 20° C. within 1.5 h to 400 mL(400 mmol) of a 1M lithium aluminium hydride solution in THF whilecooling with dry ice/isopropanol. The reaction mixture was stirredovernight at RT. While cooling with isopropanol/dry ice 120 mL of a 3:1mixture of THF:water were added dropwise at 10° C. to 20° C. Thereaction mixture was diluted with 600 mL THF. After total decompositionthe precipitate was suction filtered and washed with THF. The filtratewas evaporated down using the rotary evaporator, combined with 100 mL ofa 5% sodium hydrogen carbonate solution and extracted with 300 mL EtOAc.The organic phase was dried on sodium sulphate, suction filtered andconcentrated by rotary evaporation.

Yield: 28.7 g (96% of theory)

ESI-MS: m/z=190 (M+H)⁺

R_(f): 0.16 (silica gel, DCM/EtOH=50/1)

Step 3: 3,3-dimethylpyrrolidine hydrochloride

28.7 g (151 mmol) 1-benzyl-3,3-dimethylpyrrolidine and 2.0 g palladiumon charcoal (10%) in 100 mL methanol were hydrogenated in a hydrogenatmosphere for 3 days at 3 bars of hydrogen pressure. During this time3×300 mg palladium on charcoal (20%) were added to the reaction. Thenthe catalyst was suction filtered and the filtrate was combined with 100mL ethereal 2N HCl solution and concentrated by rotary evaporation. Theproduct was dried in vacuo in the desiccator on phosphorus pentoxide.

Yield: 20.9 g (quant.)

ESI-MS: m/z=100 (M+H)⁺

R_(f) 0.34 (silica gel, DCM/MeOH/NH₄OH=8/2/0.2)

Intermediate 36 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

1.50 g (12.7 mmol) 5-azaindole and 0.75 g Raney nickel in 70 mL ethanolwere hydrogenated in a hydrogen atmosphere at 3 bar hydrogen pressurefor 3 days at 70° C. Then the catalyst was suction filtered and thesolution was evaporated down i. vac. The residue was purified through asilica gel column. The product fractions were combined and evaporateddown using the rotary evaporator.

Yield: 620 mg (41% of theoretical)

ESI-MS: m/z=121 (M+H)⁺

R_(f) 0.12 (silica gel, DCM/MeOH/NH₄OH=80/20/2)

Intermediate 37 (6-chloropyrimidin-4-O-indol-1-yl-methanone

Under a nitrogen atmosphere 120 mg (3.00 mmol) sodium hydride (60% inmineral oil) were added batchwise to 350 mg (2.96 mmol) indole in 15 mLTHF and stirred for 30 min at RT. 500 mg (2.83 mmol)6-chloropyrimidine-4-carboxylic acid chloride was added batchwise andthen the reaction mixture was stirred for 2 h at RT. Then 50 mL EtOAcwere added and the mixture was washed with 50 mL saturated sodiumhydrogen carbonate solution (1×), 30 mL water and with 50 mL 1 Mhydrochloric acid. The organic phase was dried on magnesium sulphate,filtered and then evaporated down i. vac. The residue was purified onsilica gel. The product fractions were combined and evaporated down i.vac.

Yield: 200 mg (28% of theoretical)

MS: m/z=257/259 (M)⁺

R_(f): 0.80 (silica gel, PE/EtOAc=7/3)

Intermediate 38 (6-chloropyrimidin-4-yl)-(3-methylindol-1-yl)-methanone

Under a nitrogen atmosphere 120 mg (3.00 mmol) sodium hydride (60% inmineral oil) were added batchwise to 380 mg (2.90 mmol) 3-methylindolein 15 mL THF and the mixture was stirred for 30 min at RT. 500 mg (2.83mmol) 6-chloropyrimidine-4-carboxylic acid chloride were added batchwiseand then the reaction mixture was stirred for 2 h at RT. Then 50 mLEtOAc were added and the mixture was washed with 50 mL saturated sodiumhydrogen carbonate solution (1×), 30 mL water and with 50 mL 1 Mhydrochloric acid. The organic phase was dried on sodium sulphate,filtered and then evaporated down i. vac. The product was used in thenext step without further purification.

Yield: 300 mg (39% of theoretical)

Intermediate 39 (6-chloropyrimidin-4-yl)-(5-fluoroindol-1-yl)-methanone

Under a nitrogen atmosphere 120 mg (3.00 mmol) sodium hydride (60% inmineral oil) were added batchwise to 400 mg (2.90 mmol) 5-fluoroindolein 15 mL THF and the mixture was stirred for 30 min at RT. 500 mg (2.83mmol) 6-chloropyrimidine-4-carboxylic acid chloride were added batchwiseand then the reaction mixture was stirred for 2 h at RT. Then 50 mLEtOAc were added and the mixture was washed with 50 mL saturated sodiumhydrogen carbonate solution (1×), 30 mL water and with 50 mL 1 Mhydrochloric acid. The organic phase was dried on magnesium sulphate,filtered and then evaporated down i. vac. The residue was combined witha little EtOAc, the product precipitated was suction filtered and thefiltrate was purified on silica gel. The product fractions were combinedand evaporated down i. vac.

Yield: 70 mg (9% of theoretical)

R_(f): 0.39 (silica gel, PE/EtOAc=4/1)

Intermediate 40 6-chloro-pyrimidine-4-carboxylicacid-benzyl-(2,2,2-trifluorethyl)-amide

Step 1:benzyl-(2,2,2-trifluorethyl)-amine

2.17 g (9.4 mmol) 2,2,2-trifluoroethyltrifluoromethanesulphonate wereadded to 2.00 g (18.7 mmol) benzylamine in 50 mL xylene and the reactionmixture was refluxed overnight. After cooling the reaction mixture wassuction filtered, washed with DIPE and the filtrate was evaporated downusing the rotary evaporator. The residue was purified by flashchromatography. The product fractions were combined and evaporated downusing the rotary evaporator.

Yield: 2.30 g (65% of theory)

ESI-MS: m/z=190.0 (M+H)⁺

Step 2: 6-chloropyrimidine-4-carboxylicacid-benzyl-(2,2,2-trifluoro-ethyl)-amide

1.04 g (5.50 mmol) benzyl-(2,2,2-trifluorethyl)-amine and 5.50 mL (5.50mmol) of a 1M sodium hydroxide solution were added dropwise whilecooling with a bath of ice/ethanol to 1.00 g (5.65 mmol)6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane.The mixture was first stirred for 2 h while being cooled and then for afurther 1 h at RT. 50 mL of a saturated sodium hydrogen carbonatesolution were added and the mixture was stirred for 10 min. The organicphase was separated off, washed with water (1×30 mL) and 1M hydrochloricacid (1×50 mL), dried on sodium sulphate, filtered and evaporated downi. vac. The product was reacted further without any furtherpurification.

Yield: 1.20 g (64% of theory)

ESI-MS: m/z=330/332 (M+H)⁺

R_(t) (HPLC-MS): 1.56 min (method C)

Intermediate 411-{1-[6-(4-nitro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

150 mg (0.470 mmol) TBTU were added to 150 mg (0.44 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 75 mg (0.46 mmol) 4-nitro-2,3-dihydro-1H-indole, 100 μL (0.712mmol) triethylamine in 1.5 mL DMF and the mixture was stirred overnightat RT. The reaction mixture was poured onto 30 mL water. The aqueousphase was extracted with DCM (3×20 mL). The combined organic phases weredried on magnesium sulphate, filtered and evaporated down i. vac. Theresidue was dissolved in 3 mL DMF, filtered through a syringe filter andpurified by preparative HPLC. The product fractions were combined andlyophilised.

Yield: 30 mg (14% of theoretical)

ESI-MS: m/z=487 (M+H)⁺

R_(f): 0.54 (silica gel, eluant A)

Intermediate 421-{1-[6-(5-nitro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

150 mg (0.47 mmol) TBTU were added to 150 mg (0.44 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 75 mg (0.46 mmol) 5-nitro-2,3-dihydro-1H-indole, 100 μL and (0.712mmol) triethylamine in 1.5 mL DMF and the mixture was stirred overnightat RT. The reaction mixture was poured onto 30 mL water. Theprecipitated product was suction filtered and dried at 50° C. in theCAD.

Yield: 130 mg (61% of theoretical)

ESI-MS: m/z=487 (M+H)⁺

R_(f): 0.61 (silica gel, eluant A)

Intermediate 433-{1-[6-(3-bromo-7,8-dihydro-5H-1,6-naphthyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

90 mg (0.24 mmol) TBTU were added to 80 mg (0.20 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 70 mg (0.28 mmol)3-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine-hydrochloride and 120 μL(0.86 mmol) triethylamine in 0.9 mL DMF and the mixture was stirredovernight at RT. The reaction mixture was combined with 1 mL methanol, 1mL saturated sodium hydrogen carbonate solution and 8 mL ice water. Theprecipitate was suction filtered, washed with water and diethyl etherand dried.

Yield: 94 mg (75% of th.)

ESI-MS: m/z=592/594 (M+H)⁺

R_(t) (HPLC-MS): 3.06 min (method E)

Intermediate 44 3-ethyl-2,3-dihydro-1H-indole

Step 1: 3-ethylidene-1,3-dihydro-indol-2-one

0.85 mL (15 mmol) acetaldehyde were added dropwise to 2.0 g (15 mmol)indolin-2-one and 0.20 mL piperidine in 20 mL methanol. The reactionmixture was refluxed for 3 h and then evaporated down. The residue wastriturated in diisopropylether and suction filtered.

Yield: 2.2 g (92% of theory)

ESI-MS: m/z=158 (M−H)⁻

R_(t) (HPLC): 1.19 min (method C)

Step 2: 3-ethyl-2,3-dihydro-1H-indole

Under a nitrogen atmosphere 41 mL (41 mmol) of a 1M borane in THFsolution was added dropwise to 2.2 g (14 mmol)3-ethylidene-1,3-dihydro-indol-2-one in 50 mL THF. The reaction mixturewas refluxed for 3 h and then at 0° C. mixed with 10 mL methanolfollowed by 15 mL semi-concentrated hydrochloric acid solution. Thereaction mixture was refluxed for 3 h with stirring, cooled and washedtwice with ethyl acetate. The aqueous phase was made alkaline withaqueous 4M sodium hydroxide solution and extracted three times withethyl acetate. The organic phases were combined, dried on sodiumsulphate and evaporated down.

Yield: 1.7 g (84% of theory)

ESI-MS: m/z=148 (M+H)⁺

R_(t)(HPLC): 2.21 min (method E)

Intermediate 45 3-cyclopropylmethyl-2,3-dihydro-1H-indole

Step 1 3-cyclopropylmethylene-1,3-dihydro-indol-2-one

2.0 g (15 mmol) 1,3-dihydro-indol-2-one and 0.20 mL piperidine wereplaced in 20 mL methanol. 1.1 mL (15 mmol) cyclopropanecarboxaldehydewere added dropwise, the reaction mixture was refluxed for 3 h and thenconcentrated to dryness by rotary evaporation. The residue wastriturated with diisopropylether and the solid remaining was suctionfiltered and dried.

Yield: 2.7 g (97% of theory)

ESI-MS: m/z=186 (M+H)⁺

R_(t) (HPLC-MS): 1.27 min (method C)

Step 2 3-cyclopropylmethyl-2,3-dihydro-1H-indole

1.0 g (5.4 mmol) 3-cyclopropylmethylene-1,3-dihydro-indol-2-one wereplaced in 50 mL THF. 12 mL (12 mmol) 1M borane in THF was slowly addeddropwise. The reaction mixture was refluxed for 3 h. After cooling to RT10 mL methanol and 15 mL semi-concentrated aqueous hydrochloric acidsolution were successively added dropwise and then the mixture wasrefluxed for 3 h. After cooling to RT it was extracted with EtOAc. Theaqueous phase was made alkaline with aqueous 4M sodium hydroxidesolution and extracted once again with EtOAc. The organic phase wasdried, filtered and evaporated down.

Yield: 0.23 g (25% of theory)

ESI-MS: m/z=174 (M+H)^(+R) _(t) (HPLC-MS): 1.01 min (method C)

Intermediate 46 7,7-dimethyl-4,5,6,7-tetrahydro-thieno[3,4-c]pyridine

Step 1 methylene-(2-methyl-2-thiophene-3-yl-propyl)-amine

5.75 g (37.0 mmol) 2-methyl-2-thiophene-3-yl-propylamine and 3.61 mL(44.4 mmol) formaldehyde were stirred overnight at RT together with 2.0g molecular sieve (4 Å powder). The reaction mixture was filtered andthe filtrate was concentrated to dryness by rotary evaporation.

Yield: 6.00 g (97% of theory)

ESI-MS: m/z=168 (M+H)⁺

Step 2 7,7-dimethyl-4,5,6,7-tetrahydro-thieno[3,4-c]pyridine

6.00 g (35.9 mmol) methylene-(2-methyl-2-thiophene-3-yl-propyl)-amine,11.3 mL (45.3 mmol) 4M HCl and 11.8 mL (142 mmol) conc. HCl were stirredat RT over the weekend. The reaction mixture was made alkaline with 4MNaOH solution. The precipitate formed was suction filtered, washed withwater and dried. The substance was purified through Alox. Theproduct-containing fractions were combined and concentrated to drynessby rotary evaporation.

Yield: 740 mg (12% of theory)

R_(t) (HPLC-MS): 1.24 min (method K)

Intermediate 471,7,7-trimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridiniumtrifluoroacetate

Step 1 tert. butyl1,7,7-trimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate

2.10 g (8.36 mmol) tert. butyl7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylatewere placed in 25 mL DMF. While cooling with ice, 350 mg (8.75 mmol)sodium hydride (55%) were added. The reaction mixture was stirred for 30min, then 0.540 mL (8.67 mmol) iodomethane were added and the mixturewas stirred for 1 h at 0° C. The reaction mixture was concentrated todryness by rotary evaporation and the residue was mixed with water andextracted with EtOAc. The organic phase was dried, filtered andconcentrated to dryness by rotary evaporation. The residue was purifiedby HPLC. The product-containing fractions were combined and organicsolvent was eliminated by rotary evaporation. The aqueous residue wasextracted with DCM. The organic phase was dried, filtered andconcentrated to dryness by rotary evaporation.

Yield: 100 mg (4% of theory)

R_(t) (HPLC-MS): 3.64 min (method E)

Step 21,7,7-trimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium-trifluoro-acetate

0.10 g (0.34 mmol) tert. butyl1,7,7-trimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-5-carboxylateand 1.0 mL TFA were stirred in 2.0 mL DCM for 2 h at RT. The reactionmixture was concentrated to dryness by rotary evaporation.

Yield: 125 mg (99% of theory)

ESI-MS: m/z=166 (M+H)⁺

Intermediate 48 (1,2,3,4-tetrahydro-isoquinolin-4-yl)-methanol

0.50 mg (3.1 mmol) isoquinolin-4-yl-methanol, 75 mg platinum dioxide and3.2 mL 1N hydrochloric acid solution were hydrogenated in 50 mL methanolfor 4 h at RT under a hydrogen atmosphere at 50 psi. The reactionmixture was filtered and the filtrate was concentrated to dryness byrotary evaporation.

Yield: 0.51 g (quantitative)

R_(t) (HPLC-MS): 1.12 min (method O)

Intermediate 49

-   4,5-difluoro-3,3-dimethyl-2,3-dihydro-1H-indole

Step 1 1-acetyl-4,5-difluoro-1,3-dihydro-indol-2-one

2.00 g (11.8 mmol) 4,5-difluoro-1,3-dihydro-indol-2-one I were stirredin 6.62 mL (55.0 mmol) acetic anhydride for 2 h at 150° C. The reactionmixture was added to ice water, the precipitated solid was suctionfiltered and washed with water. The product was recrystallised from amixture of water and ethanol, suction filtered and dried.

Yield: 1.00 g (40% of theory)

ESI-MS: m/z=210 (M−H)⁻

R_(t) (HPLC-MS): 1.40 min (method C)

Step 2 4,5-difluoro-3,3-dimethyl-1,3-dihydro-indol-2-one

0.50 g (2.4 mmol) 1-acetyl-4,5-difluoro-1,3-dihydro-indol-2-one wereplaced in 10 mL DMF under argon. 0.22 g (5.1 mmol) sodium hydride (55%)were added at 0° C. and the reaction mixture was stirred for 1 h. Then0.32 mL (5.1 mmol) iodomethane were added dropwise. The reaction mixturewas stirred overnight at RT, poured onto water and extracted with EtOAc.The organic phase was dried, filtered and concentrated to dryness byrotary evaporation. The residue was purified by HPLC. Theproduct-containing fractions were combined and concentrated to drynessby rotary evaporation.

Yield: 0.15 g (32% of theory)

ESI-MS: m/z=198 (M+H)⁺

R_(t) (HPLC-MS): 1.26 min (method C)

Step 3 4,5-difluoro-3,3-dimethyl-2,3-dihydro-1H-indole

0.15 mg (0.76 mmol) 4,5-difluoro-3,3-dimethyl-1,3-dihydro-indol-2-onewere placed in 20 mL THF under argon. 0.91 mL (0.91 mmol) of a 1Mlithium aluminium hydride solution in 10 mL THF were added dropwise. Thereaction mixture was stirred for 1 h at 70° C., cooled and mixed withwater. The reaction mixture was dried, filtered and concentrated todryness by rotary evaporation.

Yield: 160 mg (quantitative)

R_(t) (HPLC-MS): 1.24 min (method C)

Intermediate 50 5,6-difluoro-3-methyl-2,3-dihydro-1H-indole

Step 1 5,6-difluoro-3-methyl-1,3-dihydro-indol-2-one

1.5 g (9.0 mmol) 5,6-difluoro-1,3-dihydro-indol-2-one were stirred with1.0 g Raney nickel in 50 mL methanol 3 h at 200° C. in an autoclave. Thecatalyst was filtered off and the filtrate was concentrated to drynessby rotary evaporation.

Yield: 1.6 g (99% of theory)

ESI-MS: m/z=184 (M+H)⁺

R_(t) (HPLC-MS): 3.2 min (method E)

Step 2 5,6-difluoro-3-methyl-2,3-dihydro-1H-indole

Under an argon atmosphere 1.6 g (8.7 mmol)5,6-difluoro-3-methyl-1,3-dihydro-indol-2-one were placed in 50 mL THF.18 mL (18 mmol) 1 M borane in THF were slowly added dropwise. Thereaction mixture was stirred for 2 h at 70° C. After cooling to RT 10 mLmethanol and 30 mL semiconc. HCl were successively added dropwise andthen the mixture was refluxed for 1 h. After cooling to RT it wasextracted with EtOAc. The aqueous phase was made alkaline with 4M NaOHsolution and extracted with DCM. The organic phase was dried, filteredand evaporated down.

Yield: 0.7 mg (47% of theory)

ESI-MS: m/z=170 (M+H)⁺

R_(t) (HPLC-MS): 2.7 min (method E)

Intermediate 51 4,5-difluoro-3-methyl-2,3-dihydro-1H-indole

Prepared analogously to 5,6-difluoro-3-methyl-2,3-dihydro-1H-indol was4,5-difluoro-3-methyl-2,3-dihydro-1H-indole from 1.50 g (8.87 mmol)4,5-difluoro-1,3-dihydro-indol-2-one.

Yield: 320 mg (41% of theory)

ESI-MS: m/z=170 (M+H)⁺

R_(t) (HPLC-MS): 2.97 min (method E)

Intermediate 525-fluoro-3-(2-methoxy-ethyl)-3-methyl-2,3-dihydro-1H-indole

Step 1 5-fluoro-3-methyl-1,3-dihydro-indol-2-one

3.0 g (20 mmol) 5-fluoro-1,3-dihydro-indol-2-one were stirred with 2.0 gRaney nickel in 50 mL methanol for 1.5 h at 200° C. in an autoclave. Thecatalyst was filtered off and the filtrate was concentrated to drynessby rotary evaporation. The residue was recrystallised from methanol,suction filtered and dried.

Yield: 2.8 g (85% of theory)

ESI-MS: m/z=166 (M+H)⁺

R_(t) (HPLC-MS): 1.1 min (method C)

Step 2 5-fluoro-3-(2-methoxy-ethyl)-3-methyl-1,3-dihydro-indol-2-one

0.50 mg (3.0 mmol) 5-fluoro-3-methyl-1,3-dihydro-indol-2-one were placedin 10 mL DMF under a nitrogen atmosphere. 0.13 g (3.0 mmol) sodiumhydride (55%) were added at 0° C. and the reaction mixture was stirredfor 30 min. Then 0.28 mL (3 mmol) 2-(bromomethyl)-methylether in 1.0 mLDMF were added dropwise. The reaction mixture was stirred overnight atRT. The substance was purified by HPLC and the product-containingfractions were combined and concentrated to dryness by rotaryevaporation.

Yield: 130 mg (19% of theory)

ESI-MS: m/z=224 (M+H)⁺

R_(t) (HPLC-MS): 1.24 min (method C)

Step 3 5-fluoro-3-(2-methoxy-ethyl)-3-methyl-2,3-dihydro-1H-indole

Under an argon atmosphere 0.12 g (0.54 mmol)5-fluoro-3-(2-methoxy-ethyl)-3-methyl-1,3-dihydro-indol-2-one wereplaced in 20 mL THF. 0.56 mL (0.56 mmol) of a 1M lithium aluminiumhydride solution in 10 mL THF were added dropwise. The reaction mixturewas stirred for 1 h at 70° C., then mixed with water and dried, filteredand concentrated to dryness by rotary evaporation.

Yield: 160 mg (quantitative)

ESI-MS: m/z=210 (M+H)⁺

R_(t) (HPLC-MS): 0.94 min (method C)

Intermediate 535′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetra-hydro-2H-[1,2′]-bipyridinyl-4′-carboxylicacid

Step 14′-chloro-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile

3.00 g (10.9 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 7.59 mL (43.6 mmol) DIPEA were placed in 90 mL ethanol. 1.89 g (10.9mmol) 4,6-dichloro-nicotinonitrile and 3 spatula tips of DMAP were addedand the reaction mixture was stirred for 4 h at RT. The precipitatedsolid was suction filtered and dried.

Yield: 3.70 g (82% of theory)

R_(t) (HPLC-MS): 1.44 min (method C)

Step 2 methyl5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylate

3.70 g (8.98 mmol)6′-chloro-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile,345 mg (0.900 mmol) PdCl₂(PhCN)₂, 498 mg (0.900 mmol) dppf and 1.52 mL(10.8 mmol) TEA were stirred in 100 mL methanol under a carbon monoxideatmosphere for 4 h at 130° C. and 25 bar. The catalyst was removed bysuction filtering and the filtrate was concentrated to dryness by rotaryevaporation.

Yield: 3.4 g (87% of theory)

R_(t) (HPLC-MS): 1.28 min (method C)

Step 35′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid

3.40 g (7.81 mmol) methyl5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylateand 6 mL of a 4M NaOH solution were stirred overnight at RT in 50 mL THFand 6 mL water. The organic solvent was eliminated by rotary evaporationand the precipitated solid was suction filtered. The filtrate wasacidified with a 4M HCl solution and the precipitated solid was suctionfiltered and dried.

Yield: 560 mg (17% of theory)

R_(t) (HPLC-MS): 1.27 min (method C)

Intermediate 54(4-chloro-pyridin-2-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone

0.50 g (3.2 mmol) 4-chloropicolinic acid, 1.1 g (3.4 mmol) TBTU and 0.91mL (6.5 mmol) TEA were placed in 10 mL DMF. 0.63 g (3.3 mmol)4,5-difluoroindoline hydrochloride were added. The reaction mixture wasstirred overnight at RT and then extracted successively with a 15%potassium carbonate solution, water, a 1M HCl solution and EtOAc. Theorganic phase was dried, filtered and concentrated to dryness by rotaryevaporation. The residue was stirred with diisopropylether and theundissolved solid was suction filtered and dried.

Yield: 850 mg (91% of theory)

ESI-MS: m/z=295/297 (Cl) (M+H)⁺

R_(t) (HPLC-MS): 1.56 min (method C)

Intermediate 55(2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone

Analogously to(4-chloro-pyridin-2-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanonethis compound was prepared from 500 mg (3.17 mmol) 2-chloroisonicotinicacid and 1.0 eq 4,5-difluoroindoline hydrochloride.

Yield: 900 mg (96% of theory)

ESI-MS: m/z=295/297 (Cl) (M+H)⁺

R_(t) (HPLC-MS): 1.44 min (method C)

Intermediate 56(2-chloro-6-methoxy-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.50 g (2.7 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.37 g (2.7 mmol)5-fluoroindoline and 0.42 mL (3 mmol) TEA were in 10 mL DMF placed. 0.97g (3.0 mmol) TBTU were added and the reaction mixture was 2 h stirred atRT. The substance was purified by HPLC. The product-containing fractionswere combined and freeze-dried.

Yield: 700 mg (86% of theory)

ESI-MS: m/z=307/309 (Cl) (M+H)⁺

R_(t) (HPLC-MS): 1.6 min (method C)

Intermediate 57

(2-chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone

1.2 g (3.8 mmol) TBTU were added at RT to 0.69 g (3.7 mmol)2-chloro-6-methoxyisonicotinic acid, 0.70 g (3.7 mmol)4,5-fluoroindoline-dihydrochloride and 1.1 mL (8.0 mmol) triethylaminein 10 mL DMF. The mixture was stirred for 2 h at RT and then poured onto200 mL of a 15% aqueous potassium carbonate solution. The precipitateformed was suction filtered, washed with water and dried.

Yield: 1.05 g (89% of theory)

ESI-MS: m/z=325/327 (M+H)⁺ (Cl)

R_(t)(HPLC): 1.66 min (method C)

Intermediate 584-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylicacid

Step 13-[1-(4-chloro-[1,3,5]triazin-2-yl)-piperidin-4-yl]-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

1.84 g (6.67 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 4.54 mL (26.7 mmol) DIPEA were placed in 50 mL ethanol. 1.00 g (6.67mmol) 2,4-dichloro-[1,3,5]triazine were added and the reaction mixturewas stirred overnight at RT. The precipitated solid was suction filteredand dried,

Yield: 1.76 g (68% of theory)

ESI-MS: m/z=389 (M+H)⁺

R_(t) (HPLC-MS): 1.35 min (method C)

Step 2 methyl4-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylate

In a CO atmosphere 400 mg (1.03 mmol)3-[1-(4-chloro-[1,3,5]triazin-2-yl)-piperidin-4-yl]-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,39.5 mg (0.1 mmol) PdCl₂(PhCN)₂, 57.0 mg (0.1 mmol) dppf and 0.173 mL(1.23 mmol) TEA in 30 mL methanol were carbonylated for 16 h at 130° C.The catalyst was suction filtered and the filtrate was concentrated todryness by rotary evaporation. The residue was mixed with isopropanoland the precipitated solid was suction filtered and dried.

Yield: 265 mg (63% of theory)

ESI-MS: m/z=413 (M+H)⁺

R_(t) (HPLC-MS): 1.22 min (method C)

Step 34-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylicacid

0.27 g (0.64 mmol) methyl4-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylateand 0.5 mL (2 mmol) of a 4M NaOH solution were stirred in 0.5 mL waterand 4.0 mL THF for 3 days at RT. The organic solvent was eliminated byrotary evaporation and the reaction mixture was combined with 0.5 mL ofa 4M HCl solution. The precipitated solid was suction filtered anddried.

Yield: 210 mg (82% of theory)

R_(t) (HPLC-MS): 0.94 min (method C)

Intermediate 596-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidine-4-carboxylicacid

Step 1 tert. butyl6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidine-4-carboxylate

0.20 g (0.73 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 0.14 mL (0.80 mmol) DIPEA were placed in 3.0 mL DMF. 0.17 g (0.74mmol) tert. butyl 6-chloro-5-methyl-pyrimidine-4-carboxylate were addedand the reaction mixture was stirred for 3 h at RT. The reaction mixturewas mixed with water and extracted with DCM. The organic phase wasdried, filtered and concentrated to dryness by rotary evaporation. Theresidue was combined with diisopropylether and the precipitated solidwas suction filtered and dried.

Yield: 140 mg (41% of theory)

ESI-MS: m/z=468 (M+H)⁺

R_(t) (HPLC-MS): 1.95 min (method C)

Step 26-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidine-4-carboxylicacid

70 mg (0.17 mmol) tert. butyl6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidin-4-carboxylate,26 mg (0.19 mmol) 5-fluoroindoline, 61 mg (0.19 mmol) TBTU and 27 μL(0.19 mmol) TEA were stirred in 1.0 mL DMF for 3 h at RT. The reactionmixture was purified by HPLC. The product-containing fractions werecombined and freeze-dried.

Yield: 58 mg (64% of theory)

ESI-MS: m/z=531 (M+H)⁺

R_(t) (HPLC-MS): 1.45 min (method C)

Intermediate 60 Isomer mixture of5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid and5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylicacid

Step 1: Isomer mixture of4′-chloro-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrileand6′-chloro-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile

1.50 g (5.15 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochlorideand 3.59 mL (20.6 mmol) DIPEA were placed in 45 mL ethanol. 891 mg (5.00mmol) 4,6-dichloro-nicotinonitrile and 3 spatula tips of DMAP were addedand the reaction mixture was stirred for 4 h at RT. The precipitatedsolid was suction filtered, washed with ethanol and dried.

Yield: 1.41 g (77% of theory)

ESI-MS: m/z=355/357 (Cl) (M+H)⁺

R_(t) (HPLC-MS): 1.15 min (method C)

Step 2 Isomer mixture of methyl5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylateand methyl5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylate

In a CO atmosphere 717 mg (2.02 mmol) of an isomer mixture of4′-chloro-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrileand6′-chloro-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile,78 mg (0.20 mmol) PdCl₂(PhCN)₂, 112 mg (0.20 mmol) dppf and 0.34 mL (2.4mmol) TEA in 30 mL methanol were carbonylated for 4 h at 130° C. and 25bar. The catalyst was removed by suction filtering and the filtrate wasconcentrated to dryness by rotary evaporation. The residue was combinedwith isopropanol and the precipitated solid was suction filtered anddried.

Yield: 112 mg (15% of theory)

R_(t) (HPLC-MS): 1.05 min (method C)

Step 3 Isomer mixture of5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]-bipyridinyl-4′-carboxylicacid and5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylicacid

272 mg (0.720 mmol) of an isomer mixture of methyl5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylateand methyl5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylatewere stirred overnight in 4.0 mL THF, 0.54 mL (2.1 mmol) of a 4M NaOHsolution and 0.54 mL water at RT. The organic solvent was eliminated byrotary evaporation and the aqueous phase was combined with 50 mL waterand 25 mL of a 4M HCl solution. The reaction mixture was stirred for onehour at RT, then the precipitated solid was suction filtered and dried.

Yield: 210 mg (80% of theory)

ESI-MS: m/z=365 (M+H)⁺

R_(t) (HPLC-MS): 3.65 min (method C)

Intermediate 614-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid

0.50 g (2.4 mmol) 2-bromopyridine-4-carboxylic acid and 1.1 g (5.0 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one were mixed andmelted for 10 min using the hot air blower. The reaction mixture wascooled, mixed with water and made basic with ammonia. It was extractedwith EtOAc. The aqueous phase was concentrated and purified by HPLC. Theproduct-containing fractions were combined and concentrated to drynessby rotary evaporation.

Yield: 200 mg (25% of theory)

ESI-MS: m/z=340 (M+H)⁺

R_(t) (HPLC-MS): 0.74 min (method C)

Intermediate 626-[4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid

Step 1: 1-benzyl-4-(2-chloro-quinolin-3-yl)-piperidin-4-ol

Under an argon atmosphere 22.3 g (136 mmol) 2-chloroquinoline in 60 mLTHF was slowly added dropwise at −78° C. to 68.0 mL (136 mmol) of a 2Mlithium diisopropylamide (in THF) solution in 280 mL THF. The reactionmixture was stirred for 1 h at −78° C. and then 24.3 mL (136 mmol)N-benzylpiperidone in 50 mL of THF were added dropwise. The reactionmixture was stirred for 40 min at −70° C. and for 3 h at RT. Thereaction mixture was cooled to −20° C., and 200 mL water were addeddropwise. The reaction mixture was allowed to come up to RT andextracted with EtOAc. The organic phase was dried, filtered andconcentrated to dryness by rotary evaporation. The product was purifiedusing an Alox column. The product-containing fractions were combined andconcentrated to dryness by rotary evaporation.

Yield: 15.5 g (32% of theory)

ESI-MS: m/z=353 (M+H)⁺

R_(t) (HPLC-MS): 1.05 min (method C)

Step 2: 3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinolin-2-ol

15.5 g (43.9 mmol) 1-benzyl-4-(2-chloro-quinolin-3-yl)-piperidin-4-olwere refluxed for 8 h in 150 mL of a 6M aqueous hydrochloric acidsolution. 100 mL water were added dropwise to the reaction mixture andthe precipitated solid was suction filtered, dried and then stirred into150 mL of a 15%, aqueous potassium carbonate solution. After theprecipitate had been suction filtered the product was obtained as a freebase and dried.

Yield: 6.20 g (45% of theory)

ESI-MS: m/z=317 (M+H)⁺

R_(t) (HPLC-MS): 1.00 min (method C)

Step 3: 3-piperidin-4-yl-1H-quinolin-2-one

5.70 g (18.0 mmol)3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinolin-2-ol were placedin 200 mL methanol. 1.00 g palladium on charcoal (10%) were added andthe reaction mixture was hydrogenated for 3 h at 50° C. under a hydrogenatmosphere. The catalyst was removed by suction filtering and the motherliquor was concentrated to dryness by rotary evaporation. The residuewas triturated with diethyl ether and the undissolved solid was suctionfiltered and dried.

Yield: 3.7 g (90% of theory)

ESI-MS: m/z=229 (M+H)⁺

R_(t) (HPLC-MS): 0.77 min (method C)

Step 4: ethyl6-[4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate

730 mg (3.91 mmol) ethyl 6-chloropyrimidine-4-carboxylate were placed in10 mL DMF. 900 mg (3.94 mmol) 3-piperidin-4-yl-1,2-dihydro-quinolin-2-oland 2.30 mL (13.4 mmol) DIPEA were added and the reaction mixture wasstirred overnight at RT. The reaction mixture was mixed with 60 mL waterand stirred for 30 min. The precipitated solid was suction filtered anddried.

Yield: 1.15 g (78% of theory)

ESI-MS: m/z=379 (M+H)⁺

R_(t) (HPLC-MS): 2.93 min (method E)

Step 5:6-[4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid

1.10 g (2.91 mmol) ethyl6-[4-(2-hydroxy-1,2-dihydro-quinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylatewere stirred overnight at RT in 20 mL THF, 1.5 mL water and 1.5 mL of a4 M NaOH solution. The organic solvent was eliminated by rotaryevaporation and the precipitated solid was suction filtered. Thefiltrate was acidified with a 4 M HCl solution and the precipitatedsolid was suction filtered and dried.

Yield: 1 g (98% of theory)

ESI-MS: m/z=351 (M+H)⁺

R_(t) (HPLC-MS): 0.98 min (method C)

Intermediate 63 6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one

Step 1: 1-benzyl-4-(2-chloro-6-methoxy-quinolin-3-yl)-piperidin-4-ol

Under an argon atmosphere 5.0 g (25 mmol) 2-chloro-6-methoxyquinoline ina small amount of THF were added dropwise at −78° C. to 14 mL (28 mmol)of a 2 M lithium diisopropylamide solution (in THF) in 50 mL THF. Thenthe mixture was stirred for 1.5 h at −78° C. and 4.5 mL (25 mmol)N-benzylpiperidone was added dropwise. The mixture was stirred for afurther 15 min with cooling before slowly being heated to RT. Thereaction mixture was stirred overnight, evaporated down and purified byflash chromatography on aluminium oxide. The product-containingfractions were combined and evaporated down.

Yield: 2.1 g (13% of theory)

ESI-MS: m/z=383 (M+H)⁺

R_(t)(HPLC): 1.14 min (method C)

Step 2:3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2-ol

1.90 g (4.96 mmol)1-benzyl-4-(2-chloro-6-methoxy-quinolin-3-yl)-piperidin-4-ol werestirred overnight at 100° C. in 25 mL of a 4N aqueous hydrochloric acidsolution. Then 15 mL of a concentrated aqueous hydrochloric acidsolution were slowly added dropwise and again the mixture was stirredovernight. After the reaction mixture had been evaporated down by halfthe remaining half was diluted with water and extracted with EtOAc. Theorganic phase was dried on sodium sulphate, filtered and evaporateddown. The residue was triturated with PE/EtOAc.

Yield: 165 mg (8% of theory)

ESI-MS: m/z=347 (M+H)⁺

Step 3: 6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one

In a hydrogen atmosphere 160 mg (0.46 mmol)3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2-ol and20 mg palladium on charcoal (10%) in 30 mL MeOH were hydrogenated for17.5 h at 50° C. at 50 psi. Then another 10 mL THF and catalyst wereadded and the mixture was hydrogenated for a further 2 h. Catalyst wasadded again and the mixture was hydrogenated overnight at 50° C. in ahydrogen atmosphere of 60 psi. After filtration of the reaction mixturethe filter cake was washed with DMF and the filtrate was evaporateddown. The residue was added to EtOAc, triturated with PE and filtered.The precipitate was washed with diisopropylether and dried.

Yield: 56 mg (35% of theory)

ESI-MS: m/z=259 (M+H)⁺

R_(t)(HPLC): 0.90 min (method C)

Intermediate 647,7-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

Step 1: tert. butyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate

20 g (0.10 mol) tert. butyl 4-oxo-piperidine-1-carboxylate in 500 mL THFwere cooled to 0° C. and mixed batchwise with 8.2 g (0.21 mol) sodiumhydride (55%). The reaction mixture was stirred for 15 min before 15 mL(0.24 mol) iodomethane was added dropwise and was then stirred overnightat RT. Then the reaction mixture was evaporated down and the residue wastaken up in diethyl ether. The organic phase was washed with water andsaturated sodium chloride solution, dried and evaporated down. Theresidue was recrystallised from PE.

Yield: 10.05 g (37% of theory)

ESI-MS: m/z=172 (M-tert.butyl+H)+

R_(t) (HPLC-MS): 1.44 min (method C)

Step 2: tert. butyl3,3-dimethyl-4-oxo-5-(2,2,2-trifluoro-acetyl)-piperidine-1-carboxylate

Under a nitrogen atmosphere 4.20 mL (4.2 mmol) of a 1 M lithiumbis(trimethylsilyl)amide solution were added to 1.00 g (3.96 mmol) tert.butyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate in 10 mL toluene at 0°C., the mixture was stirred for 1 min and then 0.56 mL (4.00 mmol)trifluoroacetic anhydride was added. The cooling bath was removed, themixture was stirred for another 2 min and combined with 10 mL water and1.2 mL acetic acid. The reaction mixture was stirred for 15 min. Afterextracting with diethyl ether the organic phase was dried and evaporateddown. The residue was purified by flash chromatography.

Yield: 300 mg (23% of theory)

ESI-MS: m/z=322 (M−H)⁻

R_(t) (HPLC-MS): 1.84 min (method C)

Step 3: tert. butyl7,7-dimethyl-3-trifluoromethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate

480 mg (1.41 mmol) tert. butyl3,3-dimethyl-4-oxo-5-(2,2,2-trifluoro-acetyl)-piperidine-1-carboxylatein 5.00 mL EtOH were combined with 0.15 mL hydrazine hydrate, 0.18 mLacetic acid and 1.00 g molecular sieve (3A) and left to stand for 48 hat RT. Then the reaction mixture was refluxed for 3 h and cooledovernight. In addition a spatula tip of p-toluenesulphonic acid was alsoadded and the mixture was refluxed first of all for 1 h and then for afurther 3 h. After cooling the reaction mixture was filtered andevaporated down. The residue was purified by flash chromatography. Amixture of tert. butyl7,7-dimethyl-3-trifluoromethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylateand tert. butyl4-hydrazone-3,3-dimethyl-5-(2,2,2-trifluoro-acetyl)-piperidine-1-carboxylatewas obtained in the ratio 3:2.

Yield: 370 mg (37% of theory)

ESI-MS: m/z=318 (M−H)⁻

Step 4:7,7-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]-pyridin-hydrochloride

0.37 g (0.52 mmol) of a mixture of tert. butyl7,7-dimethyl-3-trifluoromethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylateand tert. butyl4-hydrazone-3,3-dimethyl-5-(2,2,2-trifluoro-acetyl)-piperidine-1-carboxylatein 8.0 mL DCM was combined with 4.0 mL trifluoroacetic acid and stirredfor 2 h at RT. Then the reaction mixture was evaporated down, theresidue was dissolved in EtOH, mixed with 0.90 mL (1.1 mmol) of a 1.25molar ethanolic hydrochloric acid and co-evaporated again. The residuewas triturated with diethyl ether, suction filtered and dried.

Yield: 270 mg (77% of theory)

ESI-MS: m/z=220 (M+H)⁺

R_(t) (HPLC-MS): 0.43 min (method R)

Intermediate 65 4,4-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

Step 1: methylene-(2-methyl-2-thiophen-3-yl-propyl)-amine

5.8 g (37 mmol) 2-methyl-2-thiophene-3-yl-propylamine and 3.6 mL (44mmol) formaldehyde were stirred together with 2.0 g molecular sieve (4Apowders) overnight at RT. The reaction mixture was filtered and thefiltrate was concentrated to dryness by rotary evaporation.

Yield: 6.0 g (97% of theory)

ESI-MS: m/z=168 (M+H)⁺

Step 2: 4,4-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine

6.0 g (36 mmol) methylene-(2-methyl-2-thiophene-3-yl-propyl)-amine, 11mL (45 mmol) of a 4M HCl solution and 12 mL (0.14 mol) conc. HCl werestirred at RT over the weekend. The reaction mixture was made alkalinewith a 4M sodium hydroxide solution. The precipitate formed was suctionfiltered, washed with water and dried. The substance was purified onAlox. The product-containing fractions were combined and concentrated todryness by rotary evaporation.

Yield: 0.74 g (12% of theory)

R_(t) (HPLC-MS): 1.24 min (method K)

Intermediate 66 5,6-difluoro-2,3-dihydro-1H-indole

Under an argon atmosphere 0.30 g (1.8 mmol)5,6-difluoro-1,3-dihydro-indol-2-one were dissolved in 10 mL THF and 3.0mL of a 1 M borane in THF solution were added dropwise. Then thereaction mixture was heated for 2 h to 70° C. and then cooled. After theaddition of 3 mL MeOH a further 5 mL of a 4N aqueous hydrochloric acidsolution were added and the mixture was refluxed for 1 h. The organicphase was evaporated down, the aqueous phase was washed with DCM andthen made alkaline with a 4N aqueous sodium hydroxide solution andextracted several times with EtOAc. The combined organic phases weredried on sodium sulphate, filtered and evaporated down.

Yield: 160 mg (47% of theory)

ESI-MS: m/z=156 (M+H)⁺

R_(t) (HPLC-MS): 0.73 min (method C)

Intermediate 67 (2,3-dihydro-1H-indol-3-yl)-methanol

Step 1: ethyl 2,3-dihydro-1H-indol-3-carboxylate hydrochloride

This compound was synthesised analogously to WO 2007/054453.

Step 2: (2,3-dihydro-1H-indol-3-yl)-methanol

0.79 g (3.5 mmol) ethyl 2,3-dihydro-1H-indol-3-carboxylate were addedbatchwise at RT to 7.8 mL (7.8 mmol) of a 1 M lithium aluminium hydridesolution (in THF) in 40 mL THF and refluxed for 1 h. Then the reactionmixture was combined with water while being cooled, the precipitateformed was filtered off and the filtrate was evaporated down.

Yield: 52 mg (95% of theory)

ESI-MS: m/z=150 (M+H)⁺

R_(t) (HPLC-MS): 0.31 min (method R)

Intermediate 68 6-fluoro-2,3-dihydro-1H-indole

Under a nitrogen atmosphere 0.29 g (4.6 mmol) sodium cyanoborohydridewere added batchwise to 0.54 g (4.0 mmol) 6-fluoroindole in 5.0 mLglacial acetic acid and the mixture was stirred for 30 min. Then thereaction mixture was poured onto a 4N aqueous sodium hydroxide solutionand extracted with EtOAc. The combined organic phases were washedseveral times with saturated sodium hydrogen carbonate solution, driedon sodium sulphate and evaporated down.

Yield: 0.56 g (97% of theory)

ESI-MS: m/z=138 (M+H)⁺

R_(t) (HPLC-MS): 0.74 min (method C)

Intermediate 69 4-methyl-1,2,3,4-tetrahydro-isoquinolin hydrochloride

In a hydrogen atmosphere 0.50 g (3.5 mmol) 4-methyl-isoquinoline, 50 mgplatinum dioxide in 50 mL methanol and 3.5 mL 1M aqueous hydrochloricacid solution were hydrogenated at RT and 3 bar for 4 h. After removalof the catalyst by suction filtering the reaction mixture was evaporateddown. A mixture of educt and product was obtained, which was reactedfurther without any further purification.

Yield: 0.60 g (94% of theory)

ESI-MS: m/z=148 (M+H)⁺

R_(t) (HPLC-MS): 0.70 min (method C)

Intermediate 70 3-methyl-decahydro-quinoline hydrochloride

In a hydrogen atmosphere 500 mg (3.5 mmol) 3-methyl-decahydro-quinoline,75 mg platinum dioxide in 50 mL methanol and 3.5 mL 1M aqueoushydrochloric acid solution were hydrogenated at RT and 50 psi for 4 h.After removal of the catalyst by suction filtering the reaction mixturewas evaporated down.

Yield: 0.60 g (94% of theory)

ESI-MS: m/z=148 (M+H)⁺

R_(t) (HPLC-MS): 0.70 min (method C)

Intermediate 71 1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one

Step 1: methyl oxo-pyrrolidin-1-yl-acetate

30 mL (0.33 mol) methyloxalyl chloride in 220 mL diethyl ether wereadded dropwise to 33 mL (0.40 mol) pyrrolidine and 55 mL (0.40 mol) TEAin 500 mL diethyl ether while cooling with an ice bath. After heating toRT the mixture was stirred for a further 2 h at RT. The precipitateformed was suction filtered and the filtrate was evaporated down. Theresidue was subjected to fractional distillation under a high vacuum.

Yield: 41.8 g (82% of theory)

MS: m/z=180 (M+Na)⁺

R_(f): 0.3 (silica gel, PE/EtOAc 1/1)

Step 2: methyl (4-nitro-1H-indol-3-yl)-oxo-acetate

9.4 mL (68 mmol) diphosphoryl chloride were slowly added dropwise to 10g (62 mmol) 4-nitroindole and 11 g (68 mmol) methyloxo-pyrrolidin-1-yl-acetate with stirring and while cooling with ice.The reaction mixture was heated to RT and stirred for 3 h at RT. Thenfirst of all 10 mL MeOH were added dropwise at 0° C. and then saturatedsodium hydrogen carbonate solution was added dropwise at 0° C. Afterrepeated extraction with DCM the organic phase was dried and evaporateddown to 100 mL. This residue was left to stand at RT and the precipitateformed was suction filtered, washed and dried in the air.

Yield: 2.30 g (15% of theory)

ESI-MS: m/z=249 (M+H)⁺

R_(t) (HPLC-MS): 1.23 min (method C)

Step 3: methyl (4-nitro-2,3-dihydro-1H-indol-3-yl)-acetate

Under an argon atmosphere 16 mL (0.10 mmol) triethylsilane were slowlyadded dropwise to 2.3 g (9.3 mmol) methyl(4-nitro-1H-indol-3-yl)-oxo-acetate in 18 mL trifluoroacetic acid whilecooling with ice. Then the mixture was stirred for a further 3 h at RTand evaporated down. The residue was dried and then triturated withdiisopropylether, suction filtered and dried in the air.

Yield: 2.0 g (91% of theory)

ESI-MS: m/z=237 (M+H)⁺

R_(t) (HPLC-MS): 1.34 min (method C)

Step 4: methyl (4-amino-2,3-dihydro-1H-indol-3-yl)acetate

2.0 g (8.5 mmol) methyl (4-nitro-2,3-dihydro-1H-indol-3-yl)-acetate in70 mL MeOH were combined with 0.30 g Raney nickel and hydrogenated for 2h in a hydrogen atmosphere. The catalyst was removed by suctionfiltering and the solution was concentrated by rotary evaporation. Theresidue was immediately reacted further without further purification.

Yield: 1.80 g (quantitative)

ESI-MS: m/z=237 (M+H)⁺

R_(t) (HPLC-MS): 0.40 min (method C)

Step 5: 1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one

1.80 g (8.73 mmol) methyl (4-amino-2,3-dihydro-1H-indol-3-yl)acetate in100 mL xylene were refluxed for 30 h. The reaction mixture wasevaporated down and purified by flash chromatography. Theproduct-containing fractions were combined and evaporated down.

Yield: 0.21 g (14% of theory)

ESI-MS: m/z=175 (M+H)⁺

R_(t) (HPLC-MS): 0.03 min (method C)

Intermediate 72 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepinehydrochloride

Step 1: ethyl 3-benzylamino-propionate

25 g (0.23 mol) benzylamine and 21 g (0.21 mol) ethyl acrylate in 125 mLEtOH were stirred at RT for 15 h. Then the solvent was evaporated downand the crude product was used in the next step without furtherpurification.

Yield: 30 g (62% of theory)

ESI-MS: m/z=208 (M+H)⁺

R_(f): 0.5 (silica gel, EtOAc/PE 50%)

Step 2: ethyl4-[(benzyl-(2-ethoxycarbonyl-ethyl)-amino]-propanecarboxylate

71 g (0.36 mol) ethyl 4-bromobutyrate were slowly added dropwise at RTto 50 g (0.24 mol) ethyl 3-benzylamino-propionate and 83 g (0.60 mol)potassium carbonate in 1.0 L acetonitrile. Then the reaction mixture wasstirred for 12 h at 90° C. After cooling the reaction mixture wasdiluted with EtOAc and the organic phase was separated off. This waswashed with water and saturated sodium chloride solution and then driedon sodium sulphate. After filtration the filtrate was evaporated downand the residue was purified by flash chromatography (on aluminiumoxide).

Yield: 55 g (68% of theory)

R_(f): 0.7 (silica gel, EtOAc/PE 2%)

Step 3: 1-benzyl-azepan-4-one

Under an argon atmosphere 1.0 L xylene were heated at 145° C. for 1 to 2h with a Dean-Stark apparatus. The solvent was cooled to 65° C.,combined with 21 g (0.19 mol) potassium-tert-butoxide and heated to 145°C. for a further 1 to 2 h. Then 30 g (93 mmol) ethyl4-[benzyl-(2-ethoxycarbonyl-ethyl)-amino]-butyrate in xylene were addeddropwise over a period of 1 h to the reaction mixture and this was thenstirred for 2 to 3 h at 145° C. After cooling to 0° C. the reactionmixture was mixed with 0.45 L of a 6 N aqueous hydrochloric acidsolution, the aqueous phase was separated off and refluxed for 2 h. Thenit was cooled to 0° C. again, the reaction mixture was made alkalinewith aqueous sodium hydroxide solution and extracted with EtOAc. Thecombined organic phases were dried on sodium sulphate, filtered andevaporated down. The residue was purified by flash chromatography(aluminium oxide).

Yield: 5.5 g (29% of theory)

ESI-MS: m/z=204 (M+H)⁺

R_(f): 0.4 (silica gel, EtOAc/PE 30%)

Step 4: 1-benzyl-5-bromo-azepan-4-one-hydrobromide

5.7 mL HBr in acetic acid (33%) were added dropwise at RT to 10 g (49mmol) 1-benzyl-azepan-4-one in 28 mL acetic acid. Then another 9.5 g (60mmol) bromine were added at RT and the mixture was stirred for 1.5 h atRT. After evaporation of the reaction mixture under 35° C. the residuewas added to EtOAc and refluxed for approx. 1 h. The supernatant organicphase was decanted off from the precipitated solid, then combined againwith EtOAc and refluxed for approx. 1 h. The precipitated solid wasfiltered, washed with EtOAc and dried.

Yield: 6.0 g (34% of theory)

R_(f): 0.6 (silica gel, EtOAc/PE 30%)

Step 5:6-benzyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-hydrochloride

2.1 g (9.7 mmol) phosphorus pentasulphide and 1.9 g (41 mmol) formamidein dioxane were stirred for a total of 2.5 h at 100° C. After cooling toRT 10 g (28 mmol) 1-benzyl-5-bromo-azepan-4-one hydrobromide were addedand the mixture was stirred for 5 h at 100° C. Then the solvent wasevaporated down, the residue was added to saturated sodium bicarbonatesolution and extracted with EtOAc. The combined organic phases werewashed with water, aqueous sodium bicarbonate solution and saturatedsodium chloride solution. The organic phase was dried on sodiumsulphate, filtered and evaporated down. The residue was purified byflash chromatography. The product-containing fractions were combined andevaporated down. The free base was mixed with methanolic hydrochloricacid solution. The precipitate formed was filtered off.

Yield: 3.50 g (45% of theory)

ESI-MS: m/z=245 (M+H)⁺

R_(f): 0.5 (silica gel, MeOH/chloroform 10%)

Step 6: ethyl 4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylate

1.4 g (9.8 mmol) 1-chloroethylchloroformate were added dropwise at −20°C. to 2.0 g (8.2 mmol)6-benzyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine in 100 mL DCM andthe mixture was stirred for 30 min. The organic solvent was evaporateddown and the residue was reacted further without any furtherpurification.

Yield: 1.5 g (81% of theory)

R_(f): 0.6 (silica gel, EtOAc/PE 20%)

Step 7: 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride

1.5 g (6.6 mmol) ethyl4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylate were refluxed in50 mL MeOH for 3 h. After evaporation of the organic solvent the residuewas purified by flash chromatography. The product-containing fractionswere combined and evaporated down. The free base was mixed with 5.0 mL(12.5 mmol) of a 2.5 molar methanolic hydrochloric acid solution and theexcess solvent was evaporated down.

Yield: 0.70 g (55% of theory)

ESI-MS: m/z=155 (M+H)⁺

R_(f): 0.2 (silica gel, MeOH/chloroform 20%)

Intermediate 73 6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolinehydrochloride

Step 1: 2-(3-fluoro-phenyl)-2-methyl-propionitrile

Under an argon atmosphere 77 mL (77 mmol) of a 1M lithiumbis(trimethylsilyl)amide solution was added dropwise at −70° C. to 5.0 g(37 mmol) (3-fluoro-phenyl)-acetonitrile in 150 mL THF. The mixture wasallowed to come up to −50° C. and was then stirred at this temperaturefor 1 h. Then at −50° C. 4.8 mL (78 mmol) methyl iodide were added. Thereaction mixture was heated to RT overnight. The reaction mixture wasslowly combined with saturated aqueous ammonium chloride solution andextracted with ethyl acetate. The organic phase was dried on sodiumsulphate and evaporated down.

Yield: 5.6 g (93% of theory)

ESI-MS: m/z=163 (M+H)⁺

R_(t)(HPLC): 1.54 min (method C)

Step 2: 243-fluoro-phenyl)-2-methyl-propylamine

Under an argon atmosphere 69 mL (69 mmol) of a 1M lithium aluminiumhydride solution in THF were slowly added dropwise at 0° C. to 5.6 g (34mmol) 2-(3-fluoro-phenyl)-2-methyl-propionitrile in 40 mL THF. Thereaction mixture was stirred for 30 min at 0° C. and overnight at RT. At0° C. ethyl acetate and then water was added dropwise. The reactionmixture was filtered through Celite®, the organic phase was separatedoff and evaporated down. The residue was purified by flashchromatography.

Yield: 1.7 g (30% of theory)

ESI-MS: m/z=168 (M+H)⁺

R_(t)(HPLC): 0.86 min (method C)

Step 3:2,2,2-trifluoro-N-1-[2-(3-fluoro-phenyl)-2-methyl-propyl]-acetamide

At 0° C. 1.7 mL (12 mmol) trifluoroacetic anhydride were added dropwiseto 1.7 g (10 mmol) 2-(3-fluoro-phenyl)-2-methyl-propylamine and 5.4 mL(31 mmol) DIPEA in 35 mL dichloromethane. The reaction mixture wasstirred for 3 h at RT, mixed with water and extracted withdichloromethane. The organic phase was dried and evaporated down.

Yield: 2.7 g (97% of theory)

ESI-MS: m/z=262 (M−Hy

R_(t)(HPLC): 1.54 min (method C)

Step 4: 6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolinehydrochloride

1.0 g (3.8 mmol)2,2,2-trifluoro-N-[2-(3-fluoro-phenyl)-2-methyl-propyl]-acetamide and0.18 g (6.1 mmol) formaldehyde in 5.0 mL acetic acid and 3.5 mLconcentrated sulphuric acid were stirred for 16 h at RT. The reactionmixture was poured onto water and extracted with dichloromethane. Theorganic phase was extracted with an aqueous sodium hydrogen carbonatesolution. The organic phase was dried and evaporated down. The residuewas mixed with aqueous 0.1 M hydrochloric acid and extracted with ethylacetate. The aqueous phase was evaporated down. The product was reactedwithout further purification.

Yield: 0.14 g (17% of theory)

R_(t)(HPLC): 0.86 min (method C)

Intermediate 74 2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]

Step 1: 1′H-spiro[cyclopropane-1,4′-isoquinoline]-1-1′,3′(2′H)-dione

3.0 g (19 mmol) isoquinoline-1,3(2H,4H)-dione, 15.4 mL (0.19 mol)1-bromo-2-chloroethane and 5.1 g (37 mmol) potassium carbonate in 35 mLDMF were stirred at RT over the weekend. Then 200 mL water were addedand the mixture was extracted with ethyl acetate. The organic phase wasdried and evaporated down.

Yield: 3.0 g (86% of theory)

ESI-MS: m/z=188 (M+H)⁺

R_(t)(HPLC): 2.95 min (method E)

Step 2: 2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]

0.5 g (2.7 mmol)1′H-spiro[cyclopropane-1,4′-isoquinoline]-1′,3′(2′H)-dione in 50 mL THFwere heated to the reflux temperature of the solvent. 11 mL (11 mmol) ofa 1M borane in THF solution were added dropwise and the mixture wasrefluxed for 3 h. The reaction mixture was cooled to 0° C. and mixedwith 50 mL methanol. The reaction mixture was evaporated down, theresidue was combined with 15 mL of a 4M hydrochloric acid solution andrefluxed for 30 min. After neutralisation with 15 mL of an aqueous 4Msodium hydroxide solution the mixture was extracted twice with ethylacetate. The combined organic phases were dried and evaporated down. Theproduct was purified by HPLC. The product-containing fractions werecombined and evaporated down.

Yield: 20 mg (5% of theory)

ESI-MS: m/z=160 (M+H)⁺

R_(t)(HPLC): 0.74 min (method C)

Intermediate 75 3-(2-methoxy-ethyl)-2,3-dihydro-1H-indole

Step 1: 3-(2-methoxy-ethyl)-1,3-dihydro-indol-2-one

2.0 g (15 mmol) indolin-2-one, 5 mL (63 mmol) 2-methoxyethanol and 1.5 gRaney nickel in 20 mL THF were stirred for 4 h at 200° C. in anautoclave. After the catalyst had been filtered off the mother liquorwas evaporated down, the residue was triturated with diisopropylether,suction filtered and dried

Yield: 1.2 g (42% of theory)

ESI-MS: m/z=190 (M−H)⁻

R_(t)(HPLC): 2.87 min (method E)

Step 2: 3-(2-methoxy-ethyl)-2,3-dihydro-1H-indole

Under a nitrogen atmosphere 12.6 mL (12.6 mmol) of a 1M borane in THFsolution was added dropwise to 1.2 g (6.3 mmol)3-(2-methoxy-ethyl)-1,3-dihydro-indol-2-one in 50 mL THF. The reactionmixture was refluxed for 3 h, cooled to 0° C. and combined with 10 mLmethanol and then with 15 mL semi-concentrated hydrochloric acidsolution. The reaction mixture was refluxed for 3 h with stirring,cooled and washed twice with ethyl acetate. The aqueous phase was madealkaline with an aqueous 4M sodium hydroxide solution and extractedthree times with ethyl acetate. The organic phases were combined, driedon sodium sulphate and evaporated down.

Yield: 0.95 g (85% of theory)

ESI-MS: m/z=178 (M+H)⁺

R_(t)(HPLC): 0.76 min (method C)

Intermediate 76 5-fluoro-3-methyl-2,3-dihydro-1H-indole

Step 1: 5-fluoro-3-methyl-1,3-dihydro-indol-2-one

3.0 g (20 mmol) 5-fluoro-1,3-dihydro-indol-2-one, 50 mL methanol and 2.0g Raney nickel were stirred for 1.5 h at 200° C. in an autoclave. Afterthe catalyst had been filtered off the mother liquor was evaporated downand the residue was recrystallised from methanol.

Yield: 2.8 g (85% of theory)

ESI-MS: m/z=166 (M+H)⁺

R_(t)(HPLC): 1.1 min (method C)

Step 2: 5-fluoro-3-methyl-2,3-dihydro-1H-indole

Under an argon atmosphere 18 mL (18 mmol) of a 1M borane in THF solutionwas added dropwise to 1.5 g (9.1 mmol)5-fluoro-3-methyl-1,3-dihydro-indol-2-one in 50 mL THF. The reactionmixture was stirred for 2 h at 70° C., cooled to 0° C. and combined with10 mL methanol and then with 30 mL semi-concentrated hydrochloric acidsolution. The reaction mixture was refluxed for 1 h with stirring,cooled and the organic phase was eliminated using the rotary evaporator.The aqueous phase was extracted with ethyl acetate. The aqueous phasewas made alkaline with an aqueous 4M sodium hydroxide solution andextracted with dichloromethane. The organic phase was dried on sodiumsulphate, filtered off and evaporated down.

Yield: 0.50 g (36% of theory)

ESI-MS: m/z=152 (M+H)⁺

R_(t)(HPLC): 1.85 min (method E)

Intermediate 77(2-chloro-pyridin-4-yl)-(5,6-difluoro-2,3-dihydro-indol-1-yl)-methanone

0.35 g (2.2 mmol) 2-chloroisonicotinic acid, 0.34 g (2.2 mmol)5,6-difluoro-2,3-dihydro-1 H-indole, 0.70 mL (5.0 mmol) TEA and 10 mLDMF were mixed with 0.77 g (2.4 mmol) TBTU and stirred for 2 h at RT.The reaction mixture was purified by HPLC. The product fractions werecombined and evaporated down.

Yield: 0.45 g (69% of theory)

ESI-MS: m/z=295/297 (M+H)⁺ Cl

R_(t) (HPLC-MS): 1.5 min (method C)

Intermediate 78(2-chloro-1-oxy-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.12 g (0.43 mmol)(2-chloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and0.22 g (0.90 mmol) 3-chloroperoxybenzoic acid in 5.0 mL chloroform werestirred for 48 h at 40° C. The mixture was diluted with 50 mLdichloromethane and washed twice with 50 mL 15% aqueous potassiumcarbonate solution. The organic phase was dried and evaporated down.

Yield: 0.14 g (quantitative)

R_(t) (HPLC-MS): 1.11 min (method C)

Intermediate 79(2-chloro-pyridin-4-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-methanone

0.17 g (1.1 mmol) 2-chloroisonicotinic acid, 0.18 g (1.1 mmol)5-fluoro-3,3-dimethyl-2,3-di-hydro-1H-indole, 0.28 mL (2.0 mmol) TEA and3.0 mL DMF were combined with 0.39 g (1.2 mmol) TBTU and stirredovernight at RT. The reaction mixture was purified by HPLC.

The product fractions were combined and evaporated down.

Yield: 0.12 g (36% of theory)

ESI-MS: m/z=305/307 (M+H)⁺ Cl

R_(t) (HPLC-MS): 1.55 min (method C)

Intermediate 80(4-chloro-pyridin-2-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-methanone

0.17 g (1.1 mmol) 4-chloro-pyridine-2-carboxylic acid, 0.18 g (1.1 mmol)5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole, 0.28 mL (2.0 mmol) TEA and3.0 mL DMF were combined with 0.39 g (1.2 mmol) TBTU and stirredovernight at RT. The reaction mixture was purified by HPLC. The productfractions were combined and evaporated down.

Yield: 120 mg (36% of theory)

ESI-MS: m/z=305/307 (M+H)⁺ Cl

R_(t) (HPLC-MS): 1.66 min (method C)

Intermediate 81N-[6-chloro-4-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyridin-2-yl]-methanesulphonamide

Step 1: methyl 2-chloro-6-methanesulphonylamino-isonicotinate

Under a nitrogen atmosphere 10 g (49 mmol) methyl2,6-dichloro-isonicotinate, 5.6 g (59 mmol) methanesulphonamide, 14 g(68 mmol) potassium phosphate, 1.7 g (2.9 mmol) Xantphos and 0.90 gtris(dibenzylideneacetone)dipalladium in 300 mL dioxane were stirred for5 h at 100° C. The mixture was suction filtered through kieselguhr andevaporated down. The residue was stirred with ethanol and the solid wassuction filtered.

Yield: 4.4 g (34% of theory)

ESI-MS: m/z=265/266 (M+H)⁺ (Cl)

Step 2: 2-chloro-6-methanesulphonylamino-isonicotinic acid

0.29 g (1.1 mmol) methyl 2-chloro-6-methanesulphonylamino-isonicotinatein 5.0 mL tetrahydrofuran and 1 mL water were mixed with 79 mg (3.3mmol) lithium hydroxide and stirred overnight at RT. The reactionmixture was acidified with 1M aqueous hydrochloric acid and evaporateddown. The product was reacted without further purification.

Yield: 300 mg (quantitative)

R_(t) (HPLC-MS): 0.93 min (method C)

Step 3:N-[6-chloro-4-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyridin-2-yl]-methanesulphonamide

0.28 g (1.1 mmol) 2-chloro-6-methanesulphonylamino-isonicotinic acid,0.16 g (1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEAin 4.0 mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 2 hat RT. The reaction mixture was purified by HPLC. The product fractionswere combined and evaporated down.

Yield: 340 mg (81% of theory)

ESI-MS: m/z=370/372 (M+H)⁺ (Cl)

R_(t) (HPLC-MS): 1.4 min (method C)

Intermediate 82N-[6-chloro-4-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyridin-2-yl]-N-methyl-methane-sulphonamide

0.30 g (1.1 mmol)2-chloro-6-(methanesulphonyl-methyl-amino)-isonicotinic acid, 0.16 g(1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 4.0mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 2 h at RT.The reaction mixture was purified by HPLC. The product fractions werecombined and evaporated down.

Yield: 360 mg (83% of theory)

ESI-MS: m/z=384/386 (M+H)⁺ (Cl)

R_(t) (HPLC-MS): 1.55 min (method C)

Intermediate 83(6-chloro-pyrazin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.18 g (1.1 mmol) 6-chloro-pyrazine-2-carboxylic acid, 0.15 g (1.1 mmol)5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 3.0 mL DMFwere mixed with 0.39 g (1.2 mmol) TBTU and stirred for 1 h at RT. Thereaction mixture was mixed with water and stirred for 5 min. Theprecipitated solid was filtered, washed with water and dried.

Yield: 235 mg (66% of theory)

El-MS: m/z=277 (M+H)⁺ (Cl)

R_(t) (HPLC-MS): 1.48 min (method C)

Intermediate 84(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)-methanone

This compound was obtained analogously to(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanonefrom 0.50 g (2.7 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.44 g (2.7mmol) 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole and 0.42 mL (3.0 mmol)triethylamine in 10 mL DMF.

Yield: 0.60 g (67% of theory)

ESI-MS: m/z=335/337 (M+H)⁺ (Cl)

R_(t)(HPLC): 1.73 min (method C)

Intermediate 85(6-chloro-pyrimidin-4-yl)-(2-ethyl-2,3-dihydro-indol-1-yl)-methanone

Step 1: 1-benzenesulphonyl-1H-indole

0.89 g (22 mmol) sodium hydride (60%) were added to 2.0 g (17 mmol)indole in 30 mL THF while cooling with an ice bath and the mixture wasstirred for 15 min at this temperature. Then 2.2 mL (17 mmol)benzenesulphonic acid chloride were added and stirred overnight at RT.The reaction mixture was combined with water and EtOAc and extractedseveral times with EtOAc. The combined organic phases were dried onsodium sulphate and evaporated down.

Yield: 4.6 g (quantitative)

ESI-MS: m/z=275 (M+H)⁺

Step 2: 1-benzenesulphonyl-2-ethyl-1H-indole

Under an argon atmosphere 6.7 mL (12 mmol) of a 1.8 molar lithiumdiisopropylamide solution in THF were slowly added dropwise to 2.8 g (11mmol) 1-benzenesulphonyl-1H-indole in 25 mL THF at −78° C. Then thecooling was removed, the reaction mixture was heated to RT and stirredfor a further hour at RT. The reaction mixture was cooled to −78° C.again and combined with 1.0 mL (12 mmol) iodoethane. Then the reactionmixture was heated to RT again and stirred overnight. As the reactionwas unfinished the reaction mixture was again cooled to −78° C., mixedwith 3.3 mL (6.0 mmol) of a 1.8 molar lithium diisopropylamide solutionin THF and once the addition had ended heated to RT. Then the reactionmixture was poured onto ice water and extracted with EtOAc. The organicphase was dried on sodium sulphate and evaporated down. The residue waspurified by flash chromatography. The product-containing fractions werecombined, evaporated down and dried under HV.

Yield: 0.75 g (24% of theory)

R_(f): 0.61 (silica gel, PE/EtOAc 3/1)

Step 3: 2-ethyl-1H-indole

1.2 g (4.2 mmol) 1-benzenesulphonyl-2-ethyl-1H-indole in 10 mL EtOH werecombined with 5 mL of a (20 mmol) 4 N aqueous sodium hydroxide solutionand refluxed for 8 h. Then the solvent was eliminated using the rotaryevaporator and the residue was diluted with ice water. After acidifyingwith semi-concentrated aqueous hydrochloric acid the grease precipitatedwas extracted with ethyl acetate. The organic phase was dried on sodiumsulphate, filtered off, evaporated down and dried.

Yield: 0.66 g (quantitative)

ESI-MS: m/z=146 (M+H)⁺

Step 4: 2-ethyl-2,3-dihydro-1H-indole

0.66 g (4.2 mmol) 2-ethyl-1H-indole in 10 mL acetic acid were mixed with1.3 g (20 mmol) sodium cyanoborohydride and stirred for one day at RT.The reaction mixture was evaporated down using the rotary evaporator,combined with 20 mL aqueous 4N hydrochloric acid and stirred for 1 h atRT. While cooling with ice 45 mL of an aqueous 4N sodium hydroxidesolution were then added and the mixture was extracted with ethylacetate. The organic phase was dried on sodium sulphate, filtered,evaporated down and the residue was dried in vacuo.

Yield: 0.80 g (quantitative)

Step 5:(6-chloro-pyrimidin-4-yl)-(2-ethyl-2,3-dihydro-indol-1-yl)-methanone

0.80 g (4.5 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 30 mLDCM were cooled in a bath of ice/ethanol and mixed with 0.62 g (4.2mmol) 2-ethyl-2,3-dihydro-1H-indole in DCM and 4.7 mL (4.7 mmol) of a 1Maqueous sodium hydroxide solution. Then the mixture was stirred for 30min with cooling and for 1 h at RT. After the addition of 50 mL of asaturated sodium hydrogen carbonate solution the mixture was stirred fora further 10 min. The organic phase was separated off, washed with waterand evaporated down. The residue was purified by flash chromatography.The product-containing fractions were combined, evaporated down anddried.

Yield: 0.25 g (19% of theory)

R_(f): 0.54 (silica gel, PE/EtOAc 4/1)

Intermediate 86 3-bromo-5-(5-fluoroindoline-1-carbonyl)pyridine-1-oxide

Step 1:(5-bromo-pyridin-3-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.44 g (2.2 mmol) 5-bromonicotinic acid, 0.30 g (2.2 mmol)5-fluoroindoline, 0.75 g (2.3 mmol) TBTU and 0.60 mL (4.3 mmol) TEA werecombined in 3.0 mL DMF and stirred overnight at RT. Then the reactionmixture was added to water, the precipitate formed was suction filteredand dried.

Yield: 700 mg (quantitative)

ESI-MS: m/z=321/323 (Br) (M+H)⁺

R_(t) (HPLC-MS): 0.43 min (method C)

Step 2: 3-bromo-5-(5-fluoroindoline-1-carbonyl)pyridine-1-oxide

0.19 g (1.1 mmol) m-chloroperbenzoic acid were added to 0.32 g (0.98mmol) (5-bromo-pyridin-3-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanonein 5.0 mL DCM and the mixture was stirred for 4 h at RT. In addition, afurther 95 mg (0.55 mmol) m-chloroperbenzoic acid were added to thereaction mixture and it was stirred for 48 h at RT. Then the reactionmixture was diluted with DCM and extracted with 1N aqueous sodiumhydroxide solution. The organic phase was dried on sodium sulphate,evaporated down and dried under HV.

Yield: 330 mg (quantitative)

ESI-MS: m/z=337 (M+H)⁺

R_(t) (HPLC-MS): 1.22 min (method C)

Intermediate 87(4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

Step 1: 5-bromo-2-methylpyridine-1-oxide

39 g (0.16 mol) 3-chloroperbenzoic acid in 450 mL DCM (dried on sodiumsulphate) were added dropwise within 2 h to 25 g (0.15 mol)5-bromo-2-methylpyridine in 50 mL DCM. Then the reaction mixture wasstirred for 20 h at RT and extracted with 15% potassium carbonatesolution. The organic phase was dried on sodium sulphate and evaporateddown.

Yield: 21 g (76% of theory)

ESI-MS: m/z=337 (M+H)⁺

R_(t) (HPLC-MS): 0.75 min (method C)

Step 2: 5-bromo-2-methyl-4-nitropyridine-1-oxide

6.0 mL nitric acid were added dropwise to 6.0 mL conc. sulphuric acidwhile cooling with ice and stirring. Then 3.6 g (21 mmol)5-bromo-2-methylpyridine-1-oxide were added batchwise and the reactionmixture was stirred for 18 h at 60° C. After cooling to RT the reactionmixture was added to ice water and neutralised with 4N aqueous sodiumhydroxide solution. The precipitated solid was suction filtered anddried at 50° C.

Yield: 3.60 g (73% of theory)

ESI-MS: m/z=233 (M+H)⁺

R_(t) (HPLC-MS): 1.09 min (method C)

Step 3: 5-bromo-4-chloro-2-methylpyridine-1-oxide

4.2 mL (46 mmol) phosphorus oxychloride in 20 mL DCM were added dropwiseat 10° C. to 3.6 g (15 mmol) 5-bromo-2-methyl-4-nitropyridine-1-oxide in30 mL DCM. The reaction mixture was then refluxed for 5 h, then added toice water and adjusted to a pH of 10 with 4N aqueous sodium hydroxidesolution. The organic phase was separated off and the aqueous phase wasextracted twice more with DCM. The combined organic phases were dried onsodium sulphate and evaporated down. The residue was stirred intopetroleum ether, the precipitate formed was suction filtered and dried.

Yield: 2.60 g (76% of theory)

R_(t) (HPLC-MS): 1.08 min (method C)

Step 4: (5-bromo-4-chloro-pyridin-2-yl)-methanol

3.0 mL trifluoroacetic anhydride were added dropwise at 10° C. to 2.6 g(12 mmol) 5-bromo-4-chloro-2-methylpyridine-1-oxide in 30 mL DCM. Thereaction mixture was stirred for 5 days at RT. After the addition ofMeOH the reaction mixture was evaporated down, the residue was combinedwith 15% potassium carbonate solution and extracted several times withEtOAC. The combined organic phases were dried on sodium sulphate andevaporated down.

Yield: 2.15 g (83% of theory)

ESI-MS: m/z=222 (M+H)⁺

R_(t) (HPLC-MS): 1.10 min (method C)

Step 5: 5-bromo-4-chloro-pyridine-2-carboxylic acid

0.50 g (2.3 mmol) (5-bromo-4-chloro-pyridin-2-yl)-methanol in 8 mLacetone were added dropwise at RT to 0.71 g (4.5 mmol) potassiumpermanganate in 10 mL acetone and then the mixture was stirred for 17 hat RT. Then 10 mL isopropanol were added and the mixture was stirred fora further 5 h at RT. The precipitated manganese dioxide was suctionfiltered and washed with water. The filtrate was partially evaporateddown and the aqueous phase was adjusted to a pH of 3 with 1N aqueoushydrochloric acid solution. The precipitate formed was suction filtered.

Yield: 330 mg (62% of theory)

ESI-MS: m/z=234 (M−H)⁻

R_(t) (HPLC-MS): 1.09 min (method C)

Step 6:(5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.75 mg (2.3 mmol) TBTU were added to 0.50 g (2.1 mmol)5-bromo-4-chloro-pyridine-2-carboxylic acid, 0.29 g (2.1 mmol)5-fluoro-2,3-dihydro-1H-indole and 0.62 mL (4.4 mmol) TEA in 11 mL DMFand the mixture was stirred overnight at RT. Then the reaction mixturewas combined with water, the precipitate formed was suction filtered anddried.

Yield: 356 mg (85% of theory)

ESI-MS: m/z=355 (M+H)⁺

Step 7:(4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

Under a nitrogen atmosphere 1.3 g (8.4 mmol) sodium iodide, 80 mg (0.42mmol) copper iodide and 90 μL (0.84 mmol)N,N-dimethylene-ethylenediamine were added to 1.5 g (4.2 mmol)(5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanonein 15 mL 1,4-dioxane and the mixture was stirred for 5 days at 110° C.The reaction mixture was diluted with water, the precipitate formed wassuction filtered and dried.

Yield: 1.57 g (92% of theory)

ESI-MS: m/z=403 (M+H)⁺

R_(t) (HPLC-MS): 1.80 min (method C)

Intermediate 88(4-chloro-6-methoxy-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.55 g (2.9 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylic acid, 0.41 g(3.0 mmol) 5-fluoroindoline, 1.1 g (3.3 mmol) TBTU and 0.93 mL (6.6mmol) triethylamine in 5.0 mL DMF were stirred for 3 h at RT. Thereaction mixture was purified by HPLC. The product-containing fractionswere combined and evaporated down using the rotary evaporator.

Yield: 450 mg (50% of theory)

ESI-MS: m/z=307/309 (M+H)⁺ (Cl)

R_(t)(HPLC): 1.7 min (method C)

Intermediate 894-chloro-6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-nicotinonitrile

Under a nitrogen atmosphere 45 mg (0.50 mmol) copper cyanide were addedto 0.10 g (0.25 mmol)(4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanonein 1.5 mL DMF and the mixture was stirred for 2 h at RT. The reactionmixture was stirred overnight at 100° C. and then mixed with d-water.The precipitate formed was suction filtered and dried.

Yield: 75 mg (quantitative)

MS: m/z=301 (M+)

R_(t) (HPLC-MS): 1.65 min (method C)

Intermediate 90(4-chloro-6-methyl-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.10 g (0.58 mmol) 4-chloro-6-methyl-pyridine-2-carboxylic acid and 80mg (0.58 mmol) 5-fluoro-2,3-dihydro-1H-indole in 0.17 mL (1.2 mmol) TEAand 2.0 mL DMF were combined with 0.19 g (0.58 mmol) TBTU and stirredovernight at RT. The reaction mixture was diluted with water, theprecipitated solid was suction filtered and dried.

Yield: 125 mg (74% of theory)

ESI-MS: m/z=291 (M+H)⁺

R_(t) (HPLC-MS): 0.31 min (method C)

Intermediate 91(6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.92 g (4.9 mmol) 6-chloro-pyrimidine-4-carboxylic acid chloride in 40mL DCM were cooled in a bath of ice/acetone and mixed with 0.67 g (4.9mmol) 5-fluoro-2,3-dihydro-1H-indole. Then 5.0 mL (5.0 mmol) of a 1Naqueous sodium hydroxide solution were added dropwise and the mixturewas stirred for 1 h with cooling. 50 mL of a saturated sodium hydrogencarbonate solution were added and the mixture was stirred for a further10 min. The organic phase was separated off, extracted with a 1N aqueoushydrochloric acid solution and with water, dried and evaporated down.

Yield: 0.81 g (60% of theory)

ESI-MS: m/z=278 (M+H)⁺

R_(t) (HPLC-MS): 1.50 min (method C)

Intermediate 92(2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

2.0 g (9.5 mmol) 2,6-dichloro-pyridine-4-carboxylic acid chloride in 50mL DCM were cooled in the ice/EtOH bath and combined with 1.3 g (9.6mmol) 5-fluoro-2,3-dihydro-1H-indole. In addition 9.6 mL (9.6 mmol) of a1N aqueous sodium hydroxide solution were added dropwise and the mixturewas stirred for 2 h while being cooled and for 1 h at RT. Then 50 mL ofa saturated sodium hydrogen carbonate solution were added and themixture was stirred for a further 10 min. The organic phase wasseparated off, extracted with 1N aqueous hydrochloric acid solution andwith water, dried on sodium sulphate and evaporated down.

Yield: 2.85 g (96% of theory)

ESI-MS: m/z=311 (M+H)⁺

R_(t) (HPLC-MS): 4.57 min (method E)

Intermediate 93(3-bromo-phenyl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

0.40 g (2.0 mmol) 3-bromobenzoic acid and 0.28 g (2.0 mmol)5-fluoro-2,3-dihydro-1H-indole in 0.55 mL (4.0 mmol) TEA and 10 mL DCMwere combined with 0.64 mg (2.0 mmol) TBTU and stirred overnight at RT.The reaction mixture was extracted with saturated sodium hydrogencarbonate solution and DCM. The combined organic phases were dried onsodium sulphate, filtered and evaporated down. The residue was suspendedin MeOH, suction filtered and dried.

Yield: 475 mg (71% of theory)

ESI-MS: m/z=320 (M+H)⁺

R_(t) (HPLC-MS): 1.64 min (method C)

Intermediate 944-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylicacid

7.0 g (25 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 2.5 g (12 mmol) 4-bromopicolinic acid in 25 mL NMP were stirred for2 h at 110° C. The reaction mixture was combined with some formic acidand purified by preparative HPLC-MS. The product-containing fractionswere combined and evaporated down. The residue was stirred with MeOH,suction filtered and dried.

Yield: 0.95 g (19% of theory)

ESI-MS: m/z=397 (M+H)⁺

R_(t) (HPLC-MS): 1.25 min (method S)

Intermediate 954-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid

6.0 g (22 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 1.5 g (11 mmol) 2-fluoropyridine-4-carboxylic acid in 20 mL NMP werestirred overnight at 110° C. The reaction mixture was cooled and theprecipitate formed was suction filtered. This was stirred with water,additionally combined with 15% potassium carbonate solution andextracted several times with DCM. The aqueous phase was acidified, theprecipitate formed was suction filtered and dried.

Yield: 1.30 g (31% of theory)

ESI-MS: m/z=397 (M+H)⁺

R_(t) (HPLC-MS): 1.19 min (method S)

Intermediate 964-cyano-3-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-O-piperidin-1-yl]-benzoicacid

0.20 g (1.2 mmol) 4-cyano-3-fluorobenzoic acid and 0.53 g (2.4 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one were first ofall mixed thoroughly before being melted for 10 minutes with the hot airblower. After the reaction mixture had cooled it was taken up in water,made basic with aqueous ammonia solution and extracted several timeswith EtOAc. The aqueous phase was evaporated down and purified bypreparative HPLC-MS.

Yield: 0.20 g (41% of theory)

ESI-MS: m/z=364 (M+H)⁺

R_(t) (HPLC-MS): 1.28 min (method C)

Intermediate 971-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-iodo-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

0.50 g (1.2 mmol)(4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone,0.27 g (1.2 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.26 g (1.9mmol) potassium carbonate and 3.5 mL NMP were combined and stirred at130° C. for 10 h. After the addition of water the precipitate formed wassuction filtered and dried.

Yield: 450 mg (62% of theory)

R_(t) (HPLC-MS): 1.70 min (method C)

Intermediate 983-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-trimethylsilanylethynyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

Step 1:3-[5′-bromo-2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-diazepin-2-one

0.38 g (1.1 mmol)(5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone,0.29 g (1.1 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,0.22 g (1.6 mmol) potassium carbonate and 3.0 mL NMP were combined andstirred for 10 h at 130° C. Then the reaction mixture was combined withwater and the precipitate formed was suction filtered and dried.

Yield: 0.47 g (74% of theory)

ESI-MS: m/z=594 (M+H)⁺

R_(t)(HPLC): 1.72 min (method C)

Step 2:3-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-iodo-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-diazepin-2-one

Under a nitrogen atmosphere 91 mg (0.61 mmol) sodium-iodide, 6 mg (0.03mmol) copper iodide and 0.09 mL (0.01 mmol)N,N-dimethylene-ethylene-diamine were added to 0.18 g (0.30 mmol)3-[5′-bromo-2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-onein 1.0 mL 1,4-dioxane and the mixture was stirred overnight at 110° C.Then an additional 0.3 mL DMF was added and the reaction mixture wasstirred for a further 10 days at 110° C. After being diluted with waterthe precipitate formed was suction filtered and dried.

Yield: 194 mg (75% of theory)

purity: 75%

R_(t) (HPLC-MS): 1.79 min (method C)

Step 3:3-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-trimethylsilanylethynyl-1-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetra-hydro-benzo[d][1,3]diazepin-2-one

Under an argon atmosphere 22 mg (0.03 mmol)1,1-bis(diphenylphosphino)ferrocene-dichloro-palladium (II) and 12 mg(0.06 mmol) copper iodide were added to 0.19 g (0.23 mmol)3-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-iodo-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-onein 0.13 mL (0.91 mmol) TEA and 4.0 mL dioxane. Then another 0.42 mL (3.0mmol) trimethyl-prop-1-ynyl-silane were added and the reaction mixturewas stirred overnight at RT. After the addition of MeOH the precipitateformed was suction filtered and the filtrate was evaporated down. Theresidue was dissolved in DMF and acetonitrile and purified bypreparative HPLC-MS. The product-containing fractions were combined andevaporated down.

Yield: 35 mg (25% of theory)

R_(t) (HPLC-MS): 1.88 min (method C)

Intermediate 993-{1-[6-(5-benzyloxy-pyrrolo[3,2-b]pyridine-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

Step 1: 2-benzyloxy-5-nitro-pyridine

32 g (0.20 mol) 2-chloro-5-nitropyridine in 120 mL toluene were combinedwith 200 mL (0.20 mmol) of a 1M sodium benzylate solution inbenzylalcohol and stirred overnight at RT. The organic phase was washedwith water and saturated sodium chloride solution, dried on sodiumsulphate and the toluene was eliminated by distillation. The residue wascooled with ice, the precipitate formed was suction filtered and washedseveral times with tert.-butylmethylether.

Yield: 33.1 g (72% of theory)

Step 2: (6-benzyloxy-3-nitro-pyridin-2-yl)-acetonitrile

Under a nitrogen atmosphere 11.5 g (50 mmol)2-benzyloxy-5-nitro-pyridine and 9.2 g (55 mmol)4-chlorophenoxyacetonitrile in 100 mL DMF were added dropwise at −10° C.to 13.7 g (120 mmol) potassium tert. butoxide in 50 mL DMF. After onehour's stirring at −10° C. 120 mL of a 1N aqueous hydrochloric acidsolution were added dropwise to the reaction mixture which was thenstirred for 30 min at 0° C. The precipitate formed was suction filteredand purified by flash chromatography. The product-containing fractionswere evaporated down and the residue was combined withdiisopropylether/PE (1/1) and stirred. The precipitate formed wassuction filtered, washed with diisopropylether and dried.

Yield: 10.9 g (81% of theory)

ESI-MS: m/z=268 (M−H)⁻

R_(f): 0.75 (silica gel, DCM)

Step 3: (3-amino-6-benzyloxy-pyridin-2-yl)-acetonitrile

11 g (40 mmol) (6-benzyloxy-3-nitro-pyridin-2-yl)-acetonitrile and 1.7 gRaney nickel (washed with abs. EtOH) in 120 mL EtOH and 50 mL aceticacid were hydrogenated at RT in a hydrogen atmosphere of 3 bar. Thecatalyst was filtered off and the filtrate was evaporated down. Theresidue was combined with 30 mL water and adjusted to pH=10 with solidsodium carbonate. The aqueous phase was extracted several times withEtOAc. The combined organic phases were dried on magnesium sulphate,filtered and evaporated down. The residue was purified by flashchromatography. The product-containing fractions were combined andevaporated down.

Yield: 1.80 g (9% of theory)

ESI-MS: m/z=225 (M+H)+⁻

R_(t) (HPLC-MS): 1.10 min (method C)

Step 4:(5-benzyloxy-pyrrolo[3,2-b]pyrimidin-1-yl)-(6-chloro-pyrimidin-4-yl)-methanone

Under a nitrogen atmosphere 0.11 g (2.8 mmol) sodium hydride (60%) wereadded batchwise to 0.60 g (2.7 mmol)(3-amino-6-benzyloxy-pyridin-2-yl)-acetonitrile in 15 mL THF and themixture was stirred for 30 min at RT. 0.45 g (2.5 mmol)6-chloro-pyrimidine-4-carboxylic acid chloride were added batchwise andthe mixture was stirred for 2 h at RT. The reaction mixture was thendiluted with 50 mL EtOAc and extracted with saturated sodium hydrogencarbonate solution, water and 1N aqueous hydrochloric acid solution. Theorganic phase was dried on magnesium sulphate, filtered and evaporateddown. The residue was purified by flash chromatography. Theproduct-containing fractions were combined and evaporated down.

Yield: 420 mg (45% of theory)

ESI-MS: m/z=364 (M+H)+⁻

R_(t) (HPLC-MS): 1.79 min (method C)

Step 5:3-{1-[6-(5-benzyloxy-pyrrolo[3,2-b]pyridine-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

0.11 g (0.40 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,0.14 g (0.38 mmol)(5-benzyloxy-pyrrolo[3,2-b]pyridin-1-yl)-(6-chloro-pyrimidin-4-yl)-methanoneand 0.10 mL (0.58 mmol) DIPEA in 5 mL DMF were stirred overnight at RT.The reaction mixture was diluted with water and stirred for 30 min. Theprecipitate formed was suction filtered, washed with water and MeOH anddried.

Yield: 210 mg (91% of theory)

ESI-MS: m/z=604 (M+H)⁺

R_(t) (HPLC-MS): 1.75 min (method C

Example 1004-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylicacid

Step 1:1-[1-(2-bromo-pyrimidin-4-yl)-piperidin-4-yl]-1,3-dihydro-imidazo[4,5-b]-pyridin-2-one

1.4 g (4.8 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one-dihydrochloride,1.1 g (4.8 mmol) 2,4-dibromo-pyrimidine, a spatula tip of DMAP and 3.3mL (19.1 mmol) DIPEA in 35 mL ethanol were stirred at RT. After thereaction had ended the precipitate was suction filtered, washed with alittle ethanol and dried.

Yield: 1.6 g (90% of theory)

ESI-MS: m/z=375/377 (Br) (M+H)⁺

R_(t) (HPLC-MS): 1.08 min (method C)

Step 2: methyl4-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylate

In a carbon monoxide atmosphere 1.0 g (2.7 mmol)1-[1-(2-bromo-pyrimidin-4-yl)-piperidin-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one,0.10 g (0.27 mmol) bis-(benzonitrile)-palladium (II) chloride, 0.15 g(0.27 mmol) dppf and 0.45 mL triethylamine were carbonylated in 30 mLmethanol for 13 h at 130° C. under 25 bar of CO pressure. The reactionmixture was evaporated down and the residue was stirred with methanol.The solid was suction filtered and dried.

Yield: 0.50 g (53% of theory)

ESI-MS: m/z=355 (M+H)⁺

R_(t) (HPLC-MS): 0.83 min (method C)

Step 3:4-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylicacid

0.50 g (1.4 mmol) methyl4-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylate,1.1 mL d-water and 1.1 mL 4 M sodium hydroxide solution in 9.0 mLtetrahydrofuran was stirred overnight at RT. The organic solvent wasremoved and the residue was diluted with 250 mL water. After theaddition of 25 mL 4M hydrochloric acid solution the mixture was stirredfor 1 h. The precipitated solid was suction filtered, washed with waterand dried.

Yield: 0.37 g (53% of theory)

ESI-MS: m/z=341 (M+H)⁺

R_(t) (HPLC-MS): 0.63 min (method C)

Intermediate 101 (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine

7.0 mL (7.0 mmol) of a 1 molar di-isobutyl-aluminium hydride solution intoluene were added to 0.48 g (2.0 mmol)(S)-6-(3,5-difluorophenyl)-3,3-dimethylpiperidin-2-one in 10 mL THFwhile cooling with ice and stirred for 20 h at RT. Then the reactionmixture was refluxed for 8 h. A 1M diisobutylaluminium hydride solutionin toluene was added twice more and the mixture was refluxed for 8 h and24 h in each case. After hydrolysis of the reaction mixture theprecipitate formed was suction filtered and washed with THF. Thefiltrate was evaporated down and the residue was purified by flashchromatography (aluminium oxide).

Yield: 0.40 g (53% of theory)

ESI-MS: m/z=226 (M+H)⁺

R_(t) (HPLC-MS): 1.55 min (method C)

Intermediate 102 tert. butyl 6-chloro-5-methyl-pyrimidine-4-carboxylate

Step 1: ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate

Under a nitrogen atmosphere 28.4 g (0.27 mol) formamidine acetate in 200mL ethanol was added dropwise at −10° C. to 6.2 g (0.27 mol) sodium in150 mL ethanol. The reaction mixture was stirred for 5 min and thesuspension was suction filtered. 50 mL of diethyloxal propionate wasadded dropwise to the filtrate at −10° C. The reaction mixture wasstirred overnight in the ice bath. Then the reaction mixture wasrefluxed for 5 h. 300 mL tert.-butylmethylether were added to thesuspension and this was cooled to 3° C. The suspension was suctionfiltered and washed with TBME. The filtrate was concentrated by rotaryevaporation and the residue was combined with 300 mL ethyl acetate andCelite® and refluxed. At this temperature Celite® was suction filteredand washed with 150 mL boiling ethyl acetate. The filtrate was cooledwith stirring and seed crystals were prepared in the test tube. Thesuspension was suction filtered, washed with ethyl acetate and dried.

Yield: 7.0 g (14% of theory)

ESI-MS: m/z=181 (M−H)⁻

Step 2: 6-hydroxy-5-methyl-pyrimidine-4-carboxylic acid

5.0 g (27 mmol) ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate weredissolved in 20 mL concentrated hydrochloric acid and stirred overnightat RT. Then the reaction mixture was heated to 75° C. and stirred for 6h. The reaction mixture was cooled to 5° C., suction filtered, washedwith 2 mL concentrated hydrochloric acid and dried.

Yield: 2.8 g (66% of theory)

ESI-MS: m/z=153 (M−H)⁻

Step 3: 6-chloro-5-methyl-pyrimidine-4-carboxylic acid chloride

2.6 g (17 mmol) 6-hydroxy-5-methyl-pyrimidine-4-carboxylic acid, 6.7 mLthionyl chloride, 0.10 mL DMF in 16 mL acetonitrile were refluxedovernight. The reaction mixture was evaporated down and co-evaporatedwith toluene. The residue was combined with petroleum ether, the solidwas suction filtered and dried.

Yield: 1.0 g (31% of theory)

Step 4: tert. butyl 6-chloro-5-methyl-pyrimidine-4-carboxylate

At 0° C. a solution of 5.8 mL pyridine and 15 mL tert.-butanol in 10 mLdichloromethane was added dropwise to 6.0 g6-chloro-5-methyl-pyrimidine-4-carboxylic acid chloride in 10 mLdichloromethane. The reaction mixture was heated to RT and stirred for30 min. The reaction mixture was diluted with dichloromethane and washedsuccessively with a 2M sodium hydroxide solution, twice with a 10%aqueous citric acid solution and a sodium chloride solution. The organicphase was dried and evaporated down. The residue was taken up indichloromethane and purified by flash chromatography. Theproduct-containing fractions were evaporated down and dried.

Yield: 5.7 g (79% of theory)

Preparation of the End Compounds Example 13-{1-[3-(2,3-dihydro-indole-1-carbonyl)-phenyl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

110 mg (0.30 mmol)3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoicacid, 40 μL (0.35 mmol) 2,3-dihydro-1H-indole, 50 μL (0.36 mmol)triethylamine and 100 mg (0.31 mmol) TBTU in 2 mL DMF were stirredovernight at RT. The reaction mixture was poured onto 25 mL water. Theprecipitated product was suction filtered, washed with water, dried andby purified using a silica gel column. The product fractions werecombined and evaporated down i. vac. The residue was triturated withmethanol, suction filtered and dried at 40° C. in the CAD.

Yield: 83 mg (59% of theoretical)

ESI-MS: m/z=467 (M+H)⁺

R_(f): 0.66 (silica gel, DCM/MeOH/NH₄OH=75/25/5)

Example 23-{1-[3-(7,7-dimethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-carbonyl)-phenyl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

70.0 mg (0.19 mmol)3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoicacid, 60 mg (0.27 mmol)7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-dihydrochloride,100 μL (0.71 mmol) triethylamine and 70.0 mg (0.22 mmol) TBTU in 1 mLDMF were stirred overnight at RT. The reaction mixture was combined with1 mL methanol and 10 mL ice water. The precipitated product was suctionfiltered, washed with water and diethyl ether and purified bypreparative HPLC. The product fractions were combined and evaporateddown i. vac.

Yield: 36 mg (38% of theoretical)

ESI-MS: m/z=499 (M+H)⁺

Example 33-[4′-(2,3-dihydroindole-1-carbonyl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl]-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

100 mg (0.41 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were addedto 110 mg (0.43 mmol)(2-chloropyridin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 3.0 mL(17.4 mmol) DIPEA. The reaction mixture was refluxed for 5 h withstirring. Then 1 mL DMF were added and the mixture was stirred overnightat 130 C. After cooling water was added, the precipitate formed wassuction filtered and purified by preparative HPLC. The product fractionswere combined and evaporated down i. vac.

Yield: 10 mg (5% of theoretical)

ESI-MS: m/z=468 (M+H)⁺

R_(f): 0.74 (silica gel, eluant A)

Example 41-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1.2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one

232 mg (0.8 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloridewere added to 220 mg (0.80 mmol)(2-chloropyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and0.52 mL (3.00 mmol) DIPEA in 3.0 mL N-methylpyrrolidone. The reactionmixture was stirred for 6 h at 130° C. After 4 h 400 mg potassiumcarbonate were added and the reaction mixture was stirred for a further24 h at 130° C. Then the mixture was poured onto 100 mL water andextracted with EtOAc (3×100 mL). The combined organic phases were driedand evaporated down using the rotary evaporator. The residue waspurified by preparative HPLC. The product fractions were combined andevaporated down i. vac. The residue was triturated with 30 mL diethylether. The precipitated solid was suction filtered and dried in the air.

Yield: 20 mg (6% of theoretical)

ESI-MS: m/z=459 (M+H)⁺

R_(t) (HPLC-MS): 1.14 min (method C)

Example 53-[2′-(2,3-dihydroindole-1-carbonyl)-3,4,5,6-tetrahydro-2H-1,4′-bipyridinyl-4-yl]-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

110 mg (0.43 mmol)(4-chloro-pyridin-2-yl)-(2,3-dihydro-indol-1-yl)-methanone, 150 mg (1.0mmol) potassium carbonate and 100 mg (0.41 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 10 mL THFwere refluxed for 3 days. Then the reaction mixture was evaporated downusing the rotary evaporator, taken up in 20 mL xylene and refluxed for afurther 3 days. The solid was filtered off and the filtrate evaporateddown i. vac. The residue was dissolved in DMF and purified bypreparative HPLC. The product fractions were combined and lyophilised.

Yield: 45 mg (24% of theoretical)

ESI-MS: m/z=468 (M+H)⁺

R_(f): 0.57 (silica gel, eluant A)

Example 61-[2′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one

314 mg (1.08 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloridewere added to 300 mg (1.08 mmol)(4-chloropyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and373 mg (2.70 mmol) potassium carbonate in 5.0 mL N-methylpyrrolidone.The reaction mixture was stirred for 30 h at 130° C. Then the mixturewas poured onto 100 mL water and extracted with EtOAc (3×100 mL). Thecombined organic phases were dried and evaporated down using the rotaryevaporator. The residue was purified by preparative HPLC. The productfractions were combined and evaporated down i. vac. The residue wastriturated with 30 mL diethyl ether. The precipitated solid was suctionfiltered and dried in the air.

Yield: 190 mg (38% of theoretical)

ESI-MS: m/z=459 (M+H)⁺

R_(t) (HPLC-MS): 1.0 min (method C)

Example 76-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid benzyl-(2,2,2-trifluorethyl)-amide

44 mg (0.16 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-onewere added to 50 mg (0.15 mmol) 6-chloropyrimidine-4-carboxylicacid-benzyl-(2,2,2-trifluorethyl)-amide and 34 μL (0.20 mmol) DIPEA in 5mL DMF. The reaction mixture was stirred for 2 h at RT. The reactionmixture was purified by preparative HPLC-MS. The product fractions werecombined and evaporated down i. vac.

Yield: 62 mg (72% of theoretical)

ESI-MS: m/z=569 (M+H)⁺

R_(t) (HPLC-MS): 1.52 min (method C)

Example 83-{1-[6-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

105 mg (0.28 mmol) TBTU were added to 100 mg (0.25 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 80.0 mg (0.36 mmol)7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinedihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF andstirred overnight at RT. The reaction mixture was purified bypreparative HPLC, the product fractions were combined and thenlyophilised.

Yield: 22 mg (16% of theoretical)

ESI-MS: m/z=531 (M+H)⁺

R_(t) (HPLC): 2.51 min (method E)

Example 91-{1-[6-(7,7-dimethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one

100 mg (0.26 mmol) TBTU were added to 80 mg (0.24 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 70.0 mg (0.31 mmol)7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinedihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF andthe mixture was stirred overnight at RT. The reaction mixture waspurified by preparative HPLC, the product fractions were combined andthen lyophilised.

Yield: 34 mg (16% of theoretical)

ESI-MS: m/z=474 (M+H)⁺

R_(t) (HPLC): 2.03 min (method E)

Example 107-methoxy-3-{1-[6-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

90 mg (0.24 mmol) TBTU were added to 80 mg (0.20 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 75 mg (0.28 mmol)3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride,120.0 μL (0.86 mmol) triethylamine in 0.9 mL DMF and stirred overnightat RT. The reaction mixture was combined with 1 mL methanol, 1 mLsaturated sodium hydrogen carbonate solution and 8 mL ice water. Theprecipitate was suction filtered, washed with water and diethyl etherand dried.

Yield: 79 mg (68% of theoretical)

ESI-MS: m/z=579 (M+H)⁺

R_(t) (HPLC): 2.88 min (method E)

Example 111-{1-[6-(octahydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one

201 mg (0.69 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-on-dihydrochloridewere added to 184 mg (0.69 mmol)(6-chloropyrimidin-4-yl)-(octahydroindol-1-yl)-methanone and 488 μL (2.8mmol) DIPEA in 3 mL DMF. The reaction mixture was stirred at RT over theweekend and then purified by preparative HPLC-MS. The product fractionswere combined and the organic solvent was removed using the rotaryevaporator. The aqueous solution was neutralised with aqueous 1N NaOHsolution and the precipitate obtained was suction filtered. Theprecipitate was washed with water and dried.

Yield: 50 mg (16% of theoretical)

ESI-MS: m/z=448 (M+H)⁺

R_(t) (HPLC-MSI): 2.69 min (method E)

Example 123-{1-[6-(2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

34 μL (0.30 mmol) 2,3-dihydro-1H-indole and 90.0 mg (0.28 mmol) TBTU wasadded to 100 mg (0.27 mmol)6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 42 μL (0.30 mmol) triethylamine in 4.0 mL DMF. The mixture wasstirred for 1 h at RT and then poured onto 40 mL water. The precipitatedproduct was suction filtered. The solid was stirred with methanol,suction filtered and dried.

Yield: 65 mg (51% of theoretical)

ESI-MS: m/z=469 (M+H)⁺

R_(f): 0.48 (eluant A)

Example 131-{1-[6-(2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

350 mg (1.20 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-t]pyridin-2-one dihydrochloridewere added to 300 mg (1.16 mmol)(6-chloropyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 750 μL(4.36 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirredovernight at RT and then evaporated down i. vac. The residue waspurified by preparative HPLC. The product fractions were combined andlyophilised.

Yield: 330 mg (65% of theoretical)

ESI-MS: m/z=442 (M+H)⁺

R_(f): 0.52 (eluant A)

General Working Method 1 (GWM1) for Reacting(6-chloropyrimidin-4-yl)-(2,3-dihydroindol-1-yl)-methanone with an aminederivative

The quantity of amine derivative specified in the Table was added to 100mg (0.39 mmol)(6-chloropyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 100 μL(0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 2 hat RT. The working up could be done in various ways:

-   [A]: The reaction mixture was evaporated down using the rotary    evaporator and the residue was mixed with 20 mL water and stirred    for 30 min at RT. The precipitated product was suction filtered,    stirred with methanol and suction filtered again. The product was    dried in the CAD at 40° C.-   [B] The reaction mixture was evaporated down using the rotary    evaporator and the residue was mixed with 20 mL water and stirred    for 30 min at RT. The precipitated product was suction filtered,    stirred with diisopropylether and isopropanol and suction filtered    again. The product was dried in the CAD at 40° C.

amine derivative Example [amount of amine Analytical method Structurederivative] Yield data Example 14: GWM1[B]

3-piperidin-4-yl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 110 mg (0.41mmol) 125 mg (66% of theory) ESI-MS: m/z = 492 [M + H]⁺ R_(f) = 0.50eluant A 3-{1-[6-(2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one Example 15: GWM1[B]

5-phenyl-2-piperidin- 4-yl-2,4-dihydro- 1,2,4-triazol-3-one 100 mg (0.41mmol) 115 mg (64% of theory) ESI-MS: m/z = 448 [M + H]⁺ R_(f) = 0.53eluant A 2-{1-[6-(2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-5-phenyl-2,4-dihydro-1,2,4-triazol-3-one Example 16: GWM1[B]

1-piperidin-4-yl- 1,3-dihydro- benzimidazole-2-on  90 mg (0.41 mmol) 130mg (77% of theory) ESI-MS: m/z = 441 [M + H]⁺ R_(f) = 0.54 eluant A1-{1-[6-(2,3-dihydroindole-1-carbonyl)- pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-benzimidazole-2-one

General Working Method 2 (GWM2) for Reacting1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloridewith (6-chloropyrimidin-4-yl)-methanone derivatives:

90 mg (0.31 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloridewere added to a (6-chloropyrimidin-4-yl)-methanone derivative and 100 μL(0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 2 hat RT, then evaporated down and the residue was combined with 20 mLwater and stirred for 30 min at RT. The precipitated product was suctionfiltered and purified by flash chromatography. The product fractionswere combined and evaporated down using the rotary evaporator. Theresidue was triturated with diisopropylether and suction filtered. Theproduct was dried at 40° C. in the CAD.

6-chloropyrimidin-4- yl derivative [amount of 6-chloro- pyrimidin-4-ylAnalytical Example Structure derivative] Yield data Example 17:

(6-chloropyrimidin-4- yl)-(1,3-dihydro- isoindol-2-yl)- methanone 100 mg(0.39 mmol) 30 mg (22% of theory) ESI-MS: m/z = 442 [M + H]⁺ R_(f) =0.66 eluant A 1-{1-[6-(1,3-dihydro-isoindole-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo [4,5-b]pyridin-2-one Example18:

(6-chloropyrimidin-4- yl)-(3,4-dihydro-1H- isoquinolin-2-yl)- methanone100 mg (0.37 mmol) 35 mg (25% of theory) ESI MS: m/z = 456 [M + H]⁺R_(f) = 0.56 eluant A 1-{1-[6-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one Example 19:

(6-chloropyrimidin-4- yl)-(3,4-dihydro-2H- quinolin-1-yl)- methanone 100mg (0.37 mmol) 25 mg (18% of theory) ESI-MS: m/z = 456 [M + H]⁺ R_(f) =0.56 eluant A 1-{1-[6-(3,4-dihydro-2H-quinoline-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3- dihydro-imidazo[4,5-b]pyridin-2-one

Example 201-{1-[6-(1,2,4,5-tetrahydro-3-benzazepin-3-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one

100.0 mg (0.29 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 50.0 mg (0.34 mmol) 2,3,4,5-tetrahydro-1H-3-benzazepine, 100 μL(0.71 mmol) triethylamine and 100.0 mg (0.31 mmol) TBTU in 1.5 mL DMFwere stirred overnight at RT. The reaction mixture was filtered througha syringe filter and the solution was purified by preparative HPLC. Theproduct fractions were combined and lyophilised.

Yield: 60 mg (44% of theoretical)

ESI-MS: m/z=470 (M+H)⁺

R_(f): 0.50 (silica gel, eluant A)

General Working Method 3 (GWM3) for Reacting5-phenyl-2-piperidin-4-yl-2,4-dihydro-1,2,4-triazol-3-one with(6-chloropyrimidin-4-yl)-methanone derivatives

100 mg (0.41 mmol)5-phenyl-2-piperidin-4-yl-2,4-dihydro-1,2,4-triazol-3-one were added toa corresponding amount of a (6-chloropyrimidin-4-yl)-methanonederivative (see Table) and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. Thereaction mixture was stirred for 2 h at RT, then evaporated down and theresidue was combined with 20 mL water and stirred for 30 min at RT. Theprecipitated product was suction filtered, stirred with methanol andsuction filtered again. The product was dried at 40° C. in the CAD.

6-chloropyrimidin- 4-yl derivative [amount of 6-chloro- pyrimidin-4-ylAnalytical Example Structure derivative] Yield data Example 21:

(6-chloropyrimidin- 4-yl)-(1,3-dihydro- isoindol-2-yl)- methanone 100 mg(0.39 mmol) 95 mg (53% of theory) ESI-MS: m/z = 468 [M + H]⁺ R_(f) =0.57 eluant A 2-{1-[6-(1,3-dihydro-isoindole-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-5-phenyl-2,4-dihydro-1,2,4-triazol-3-on Example 22:

(6-chloropyrimidin- 4-yl)-(3,4-dihydro- 1H-isoquinolin-2- yl)-methanone100 mg (0.37 mmol) 60 mg (34% of theory) ESI-MS: m/z = 482 [M + H]⁺R_(f) = 0.58 eluant A 2-{1-[6-(3,4-dihydro-1H-isoquinolin-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-5-phenyl-2,4-dihydro-1,2,4-triazol-3-one

General Working Method 4 (GWM4) for Reacting3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one with(6-chloropyrimidin-4-yl)-methanone derivatives

100 mg (0.37 mmol)3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one were added toa corresponding amount of a (6-chloropyrimidin-4-yl)-methanonederivative (see Table) and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. Thereaction mixture was stirred for 2 h at RT, then evaporated down i. vac.and the residue was combined with 20 mL water and stirred for 30 min atRT. The precipitated product was suction filtered, stirred with methanoland suction filtered again. The product was dried at 40° C. in the CAD.

6-chloropyrimidin- 4-yl)-(derivatives [amount of 6-chloro- pyrimidineAnalytical Example Structure derivative] Yield data Example 23:

(6-chloropyrimidin- 4-yl)-(1,3-dihydro- isoindol-2-yl)- methanone  95 mg(0.37 mmol) 130 mg (72% of theory) ESI-MS: m/z = 492 [M + H]⁺ R_(f) =0.55 eluant A 3-{1-[6-(1,3-dihydro-isoindole-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one Example 24:

(6-chloropyrimidin- 4-yl)-(3,4-dihydro- 1H-isoquinolin-2-yl)- methanone100 mg (0.37 mmol) 120 mg (65% of theory) ESI MS: m/z = 506 [M + H]⁺R_(f) = 0.56 eluant A 3-{1-[6-(3,4-[6-1H-isoquinolin-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one Example 25:

(6-chloro-pyrimidin- 4-yl)-(3,4-dihydro- 2H-quinolin-1-yl)- methanone100 mg (0.37 mmol)  55 mg (30% of theory) ESI-MS: m/z = 506 [M + H]⁺R_(f) = 0.53 eluant A 3-{1-[6-(3,4-dihydro-2H-quinoline-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

Example 263-{1-[6-(2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

110 mg (0.4 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-onewere added to 100 mg (0.39 mmol)(6-chloropyrimidin-4-yl)-(2,3-dihydroindol-1-yl)-methanone and 100 μL(0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 2 hat RT and then evaporated down i. vac. The residue was combined with 20mL water and stirred for 30 min at RT. The precipitated product wassuction filtered, stirred with methanol, suction filtered again anddried at 40° C. in the CAD.

Yield: 35 mg (18% of theoretical)

ESI-MS: m/z=499 (M+H)⁺

R_(f): 0.70 (silica gel, eluant A)

Example 277-chloro-3-{1-[6-(2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

110 mg (0.36 mmol)7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-onewere added to 87.6 mg (0.34 mmol)(6-chloropyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 63 μL(0.37 mmol) DIPEA in 2.5 mL DMF. The reaction mixture was stirredovernight at RT, then concentrated by rotary evaporation using therotary evaporator and purified by preparative HPLC. The correspondingproduct fractions were combined and evaporated down using the rotaryevaporator. The residue was taken up in DMF and combined with methanol.The substance was precipitated, suction filtered, washed with a littlemethanol and dried.

Yield: 117 mg (69% of theoretical)

ESI-MS: m/z=503/505 (M+H)⁺

R_(t) (HPLC-MS): 3.87 min (method E)

Example 281-{1-[6-(5-chloro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

80 mg (0.27 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one(dihydrochloride) were added to 100 mg (0.34 mmol)(5-chloro-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirredfor 22 h at RT and then evaporated down i. vac. The residue was combinedwith 20 mL water and stirred for 30 min at RT. The precipitated productwas suction filtered. The purification was carried out using a silicagel column. The product fractions were combined and the solvent waseliminated using the rotary evaporator. The residue was stirred withwater, suction filtered and dried.

Yield: 30 mg (19% of theoretical)

ESI-MS: m/z=476/478 (M+H)⁺

R_(t) 0.44 (silica gel, eluant A)

General Working Method 5 (GWM5) for Reacting(5-chloro-2,3-dihydro-indol-1-O-(6-chloropyrimidin-4-yl)-methanone withamines

A corresponding amount of an amine derivative (see Table) was added to100 mg (0.34 mmol)(5-chloro-2,3-dihydro-indol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirredfor 2 h at RT, then evaporated down i. vac. and the residue was mixedwith 20 mL water and stirred for 30 min at RT. The precipitated productwas suction filtered, stirred with methanol and suction filtered again.The product was dried in the CAD at 40° C. The following Examples weresynthesised according to this general working method:

amine [amount of Analytical Example Structure amine] Yield data Example29:

3-piperidin-4-yl- 1,3,4,5-tetrahydro- 1,3-benzodiazepin- 2-one  90 mg(0.37 mmol) 145 mg (85% of theory) ESI MS: m/z = 503/505 [M + H]⁺ R_(f)= 0.72 eluant A 3-{1-[6-(5-chloro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one Example 30:

3-piperidin-4-yl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one  90 mg(0.34 mmol) 115 mg (64% of theory) ESI-MS: m/z = 526/528 [M + H]⁺ R_(f)= 0.50 eluant A 3-{1-[6-(5-chloro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-c]quinolin-2-one Example 31:

5-phenyl-2- piperidin-4-yl-2,4- dihydro-1,2,4- triazol-3-one  85 mg(0.35 mmol)  65 mg (38% of theory) ESI-MS: m/z = 502/504 [M + H]⁺ R_(f)= 0.54 eluant A 2-{1-[6-(5-chloro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-5-phenyl-2,4-dihydro-1,2,4-triazol-3-one Example 32:

7-methoxy-3- piperidin-4-yl- 1,3,4,5-tetrahydro- 1,3-benzodiazepin-2-one 100 mg (0.36 mmol) 120 mg (66% of theory) ESI-MS: m/z = 533/535[M + H]⁺ R_(f) = 0.68 eluant A3-{1-[6-(5-chloro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

Example 331-{1-[6-(5-bromo-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

70 mg (0.24 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloridewere added to 100 mg (0.30 mmol)(5-bromo-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirredfor 22 h at RT and then evaporated down i. vac. The residue was combinedwith 20 mL water and stirred for 30 min at RT. The precipitated productwas suction filtered. The purification was carried out using a silicagel column. The product fractions were combined and the solvent waseliminated using the rotary evaporator. The residue was stirred withwater, suction filtered and dried at 40° C. in the CAD.

Yield: 55 mg (36% of theoretical)

ESI-MS: m/z=520/522 (M+H)⁺

R_(f): 0.44 (silica gel, eluant A)

General Working Method 6 (GWM6) for Reacting(5-bromo-2,3-dihydro-indol-1-yl)-(6-chloropyrimidin-4-yl)-methanone withamines

0.30 mmol of an amine derivative were added to 100 mg (0.30 mmol)(5-bromo-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirredfor 2 h at RT, then evaporated down i. vac. and the residue was combinedwith 20 mL water and stirred for 30 min at RT. The precipitated productwas suction filtered, stirred with methanol and suction filtered again.The product was dried in the CAD at 40° C. The following Examples weresynthesised according to this general working method:

amine [amount Analytical Example Structure of amine] Yield data Example34:

3-piperidin-4-yl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one 80 mg (0.30mmol) 85 mg (51% of theory) ESI-MS: m/z = 570/572 [M + H]⁺ R_(f) = 0.43eluant A -{1-[6-(5-bromo-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one Example 35:

5-phenyl-2- piperidin-4-yl- 2,4-dihydro-1,2,4- triazol-3-one 75 mg (0.30mmol) 30 mg (19% of theory) ESI-MS: m/z = 546/548 [M + H]⁺ R_(f) = 0.52eluant A 2-{1-[6-(5-bromo-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-5-phenyl-2,4-dihydro-1,2,4-triazol-3-one

Example 361-{1-[6-(5-fluoro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

100 mg (0.294 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 42 mg (0.31 mmol) 5-fluoro-2,3-dihydro-1H-indole, 100 mg (0.311mmol) TBTU and 45 μL (0.320 mmol) triethylamine in 10 mL DMF werestirred overnight at RT. The reaction mixture was evaporated down usingthe rotary evaporator. The residue was dissolved in 3 mL DMF andpurified by preparative HPLC-MS. The product fractions were combined andlyophilised.

Yield: 50 mg (37% of theoretical)

ESI-MS: m/z=460 (M+H)⁺

R_(f) 0.52 (eluant A)

Example 371-{1-[6-(5-fluoro-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-t]pyridin-2-one

100 mg (0.294 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-t]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 50 mg (0.300 mmol) 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole,106.1 mg (0.33 mmol) TBTU and 84 μL (0.60 mmol) triethylamine in 2 mLDMF were stirred overnight at RT. The reaction mixture was purified bypreparative HPLC-MS. The product fractions were combined andlyophilised.

Yield: 100 mg (70% of theoretical)

ESI-MS: m/z=488 (M+H)⁺

R_(t) (HPLC): 3.5 min (method C)

Example 38 Methyl(5-fluoro-1-{6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-2,3-dihydro-1H-indol-3-yl)-acetate

150 mg (0.441 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 105 mg (0.500 mmol) methyl(5-fluoro-2,3-dihydro-1H-indol-3-yl)-acetate, 148 mg (0.460 mmol) TBTUand 112 μL (0.80 mmol) triethylamine in 2 mL DMF were stirred for 3 h atRT. The reaction mixture was purified by preparative HPLC-MS without anyfurther working up. The product fractions were combined and lyophilised.

Yield: 116 mg (50% of theoretical)

ESI-MS: m/z=532 (M+H)⁺

R_(t) (HPLC-MS): 1.32 min (method C)

Example 391-{1-[6-(4,5-difluoro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-t]pyridin-2-one

100 mg (0.294 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 60.0 mg (0.313 mmol) 4,5-difluoroindoline hydrochloride, 100 mg(0.311 mmol) TBTU and 45 μL (0.32 mmol) triethylamine in 10 mL DMF werestirred overnight at RT. The reaction mixture was concentrated by rotaryevaporation using the rotary evaporator, with heating, under reducedpressure. The residue was dissolved in 3 mL DMF and purified bypreparative HPLC. The product fractions were combined and lyophilised.

Yield: 85 mg (61% of theoretical)

ESI-MS: m/z=478 (M+H)⁺

R_(f) 0.52 (eluant A)

Example 401-{1-[6-(3,3-dimethyl-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

70 mg (0.21 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 30.33 mg (0.21 mmol) 3,3-dimethyl-2,3-dihydro-1H-indole, 71 mg(0.22 mmol) TBTU and 56 μL (0.40 mmol) triethylamine in 2 mL DMF werestirred overnight at RT. The mixture was separated by preparative HPLC.The product fractions were combined and lyophilised.

Yield: 55 mg (57% of theoretical)

ESI-MS: m/z=470 (M+H)⁺

R_(t) (HPLC-MS): 3.5 min (method K)

Example 411-(1-{6-[3-(3-pyrrolidin-1-yl-propyl)-2,3-dihydroindole-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

140 mg (0.41 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 94.4 mg (0.41 mmol)3-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-1H-indole, 138.2 mg (0.43 mmol)TBTU and 112 μL (0.8 mmol) triethylamine in 4 mL DMF were stirredovernight at RT. The mixture was separated by preparative HPLC. Theproduct fractions were combined and lyophilised.

Yield: 55 mg (24% of theoretical)

ESI-MS: m/z=553 (M+H)⁺

R_(t) (HPLC-MS): 1.0 min (method C)

Example 42 Ethyl1-{6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-2,3-dihydro-1H-indole-2-carboxylate

150 mg (0.44 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]pyrimidine-4-carboxylicacid, 110 mg (0.48 mmol) ethyl 2,3-dihydro-1H-indole-2-carboxylatehydrochloride, 150.0 mg (0.47 mmol) TBTU and 150 μL (1.1 mmol)triethylamine in 2 mL DMF were stirred overnight at RT. The mixture wasfiltered through a syringe filter and the solution was purified bypreparative HPLC. The product fractions were combined and lyophilised.

Yield: 35 mg (16% of theoretical)

ESI-MS: m/z=514 (M+H)⁺

R_(t) 0.55 (silica gel, eluant A)

Example 431-(1-(6-(spiro[cyclobutan-1,3′-indolin]-1′-ylcarbonyl)pyrimidin-4-yl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

214 mg (0.63 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 100 mg (0.628 mmol) spiro[cyclobutane-1,3′-indoline], 212 mg (0.66mmol) TBTU and 168 μL (1.20 mmol) triethylamine in 4 mL DMF were stirredovernight at RT. The mixture was separated by preparative HPLC. Theproduct fractions were combined and the acetonitrile was removed usingthe rotary evaporator. The precipitated substance was suction filtered,washed with 20 mL water and dried in the CAD at 50° C.

Yield: 187 mg (62% of theoretical)

ESI-MS: m/z=482 (M+H)⁺

R_(t) (HPLC-MS): 1.37 min (method C)

General Working Method 7 (GWM7) for Reacting6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid with amines

100 mg (0.31 mmol) TBTU were added to 100 mg (0.29 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, a corresponding amount of an amine (see Table) and 45 μLtriethylamine in 10.0 mL DMF and stirred overnight at RT. The reactionmixture was evaporated down using the rotary evaporator. The residue wasdissolved in 3 mL DMF and purified by preparative HPLC. The productfractions were combined and then lyophilised.

[amount of amine] Analytical Example Structure amine Yield data Example44:

40 mg (0.30 mmol) 3-methyl- phenethylamine 48 mg (36% of theory) ESI-MS:m/z = 458 [M + H]⁺ R_(f) = 0.57 eluant A6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4- carboxylic acid(2-m-tolylethyl)-amide Example 45:

50 mg (0.31 mmol) 1,1-dimethyl-2-m- tolylethylamine 72 mg (51% oftheory) ESI-MS: m/z = 486 [M + H]⁺ R_(f) = 0.66 eluant A[6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid(1,1-dimethyl-2-m-tolyl-ethyl)-amide Example 46:

40 μL (0.31 mmol) 2-methyl-2,3- dihydro-1H-indole 91 mg (68% of theory)ESI-MS: m/z = 456 [M + H]⁺ R_(f) = 0.59 eluant A1-{1-[6-(2-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one Example 47:

40 μL (0.31 mmol) 5-methyl-2,3- dihydro-1H-indole 80 mg (60% of theory)ESI-MS: m/z = 456 [M + H]⁺ R_(f) = 0.40 eluant A1-{1-[6-(5-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one

Example 481-{6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-2,3-dihydro-1H-indole-2-carboxylicacid

107 mg (0.31 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 65.0 mg (0.40 mmol) 2,3-dihydro-1H-indole-2-carboxylic acid, 107.0mg (0.33 mmol) TBTU and 100 μL (0.71 mmol) triethylamine in 10 mL DMFwere stirred overnight at RT. The mixture was evaporated down i. vac.and the residue was dissolved in 5 mL DMF. The purification was carriedout by preparative HPLC. The product fractions were combined andlyophilised.

Yield: 10 mg (7% of theoretical)

ESI-MS: m/z=486 (M+H)⁺

R_(f) 0.07 (silica gel, eluant A)

General Working Method 8 (GWM8) for Reacting6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid with amines

100 mg (0.31 mmol) TBTU were added to 100 mg (0.29 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, a corresponding amount of amine (see Table) and 100 μL (0.71 mmol)triethylamine in 1.5 mL DMF and the mixture was stirred overnight at RT.Working up was carried out by two different methods:

-   [A] The reaction mixture was diluted with 5 mL water and purified by    preparative HPLC. The product fractions were combined and then    lyophilised.-   [B] The reaction mixture was filtered through a syringe filter and    purified by preparative HPLC. The product fractions were combined    and then lyophilised.

Example [amount of amine] Analytical method Structure amine Yield dataExample 49: GWM 8[A]

55 mg (0.3 mmol) 3-phenyl- pyrrolidine- hydrochloride 55 mg (40% oftheory) ESI-MS: m/z = 470 [M + H]⁺ R_(f) = 0.59 eluant A1-{1-[6-(3-phenyl-pyrrolidin-1- carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one Example 50: GWM 8[A]

41 mg (0.3 mmol) 3,3-dimethyl- pyrrolidine- hydrochloride 65 mg (53% oftheory) ESI-MS: m/z = 422 [M + H]⁺ R_(f) = 0.57 eluant A1-{1-[6-(3,3-dimethylpyrrolidin-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one Example 51: GWM 8[A]

45 mg (0.30 mmol) 2-(methylethyl)- pyrrolidine- hydrochloride 65 mg (51%of theory) ESI-MS: m/z = 436 [M + H]⁺ R_(f) = 0.57 eluant A1-{1-[6-(2-isopropyl-pyrrolidin-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one Example 52: GWM 8[B]

40 mg (0.36 mmol) 6-aza- spiro[3,4]octane 40 mg (31% of theory) ESI-MS:m/z = 434 [M + H]⁺ R_(f) = 0.61 eluant A1-{1-[6-(6-aza-spiro[3,4]octane-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one Example 53: GWM 8[B]

40 mg (0.33 mmol) 2,3-dihydro-1H- pyrrolo[3,2- c]pyridine 60 mg (46% oftheory) ESI-MS: m/z = 443 [M + H]⁺ R_(f) = 0.50 eluant A1-{1-[6-(2,3-dihydro-pyrrolo[3,2-c]pyridin-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one

General Working Method 9 (GWM9) for Reacting6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid with amines

62 mg (0.19 mmol) TBTU were added to 60 mg (0.18 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 0.18 mmol amine and 52 μL (0.37 mmol) triethylamine in 1.5 mL DMFand the mixture was stirred for 4 h at RT. The reaction mixture waspurified by preparative HPLC. The product fractions were combined andlyophilised.

[amount of amine] Analytical Example Structure amine Yield data Example54:

31 mg (0.18 mmol) 4,4-dimethyl- piperidine 16 mg (21% of theory) ESI-MS:m/z = 436 [M + H]⁺ R_(t) = 1.12 min method C1-{1-[6-(4,4-dimethyl-piperidine-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one Example 55:

28 mg (0.18 mmol) 4.4-dimethyl- 1,2,3,4-tetrahydro- isoquinoline 35 mg(41% of theory) ESI-MS: m/z = 484 [M + H]⁺ R_(t) = 1.25 min method C1-{1-[6-(4.4-dimethyl-3,4-dihydro-1 H-isoquinolin-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one Example 56:

24.5 mg (0.18 mmol) 4,5,6,7-tetrahydro- thieno[3,2- c]pyridine 36 mg(44% of theory) ESI-MS: m/z = 462 [M + H]⁺ R_(t) = 1.13 min method C1-{1-[6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one Example 57:

25 mg (0.18 mmol) 4,5,6,7-tetrahydro- thieno[2,3- c]pyridine 32 mg (39%of theory) ESI-MS: m/z = 462 [M + H]⁺ R_(t) = 1.15 min method C1-{1-[6-(4.7-dihydro-5H-thieno[2,3-c]pyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

Example 581-{1-[6-(4-amino-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

Under a hydrogen atmosphere 130 mg (0.27 mmol)1-{1-[6-(4-nitro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-oneand 25 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixturemethanol:THF (15 mL of each) at RT and 3 bar hydrogen pressure. Then thecatalyst was eliminated by suction filtering and the residue was washedwith 50 mL DMF. The filtrate was evaporated down i. vac., the residuewas stirred with methanol and suction filtered. The solid was dried at50° C. in the CAD.

Yield: 40 mg (33% of theoretical)

ESI-MS: m/z=457 (M+H)⁺

R_(f): 0.53 (silica gel, eluant A)

Example 591-{1-[6-(5-amino-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

Under a hydrogen atmosphere 30 mg (0.06 mmol)1-{1-[6-(5-nitro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneand 10 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixturemethanol:THF (5 mL each) at RT and 3 bar hydrogen pressure. Then thecatalyst was removed by suction filtering and the filtrate wasevaporated down i. vac. The residue was dissolved in 1 mL DMF, filteredthrough a syringe filter and purified by preparative HPLC. The productfractions were combined and lyophilised.

Yield: 1 mg (4% of theoretical)

ESI-MS: m/z=457 (M+H)⁺

R_(f): 0.51 (silica gel, eluant A)

Example 603-{1-[6-(7,8-dihydro-5H-1,6-naphthyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

Under a hydrogen atmosphere 77 mg (0.12 mmol)3-{1-[6-(3-bromo-7,8-dihydro-5H-1,6-naphthyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 40 mg palladium on charcoal (10%) were hydrogenated in 10 mLmethanol at 50° C. under 50 psi hydrogen pressure. Then the catalyst wasremoved by suction filtering and the filtrate was evaporated down i.vac. The residue was purified by preparative HPLC. The product fractionswere combined and lyophilised.

Yield: 27 mg (43% of theoretical)

ESI-MS: m/z=514 (M+H)⁺

R_(t) (HPLC-MS): 2.19 min (method E)

Example 616-[4-(2-oxo-2,3-dihydro-imidazo[4,5-t]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid-indan-2-ylamide

100 mg (0.29 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 40.0 mg (0.30 mmol) indan-2-ylamine, 100 mg (0.31 mmol) TBTU and45 μL (0.32 mmol) triethylamine in 10 mL DMF were stirred overnight atRT. The mixture was evaporated down i. vac., the residue was dissolvedin 3 mL DMF and purified by preparative HPLC. The product fractions werecombined and lyophilised.

Yield: 62 mg (46% of theoretical)

ESI-MS: m/z=456 (M+H)⁺

R_(f) 0.74 (silica gel, eluant A)

Example 626-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid-phenylamide

120.0 mg (0.30 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 30 μL (0.33 mmol) aniline, 120.0 mg (0.37 mmol) TBTU and 100 μL(0.71 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. Themixture was filtered through a syringe filter and purified bypreparative HPLC. The product fractions were combined and lyophilised.

Yield: 65 mg (46% of theoretical)

ESI-MS: m/z=473 (M+H)⁺

R_(f) 0.57 (silica gel, eluant A)

Example 631-{1-[6-(indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

100 mg (0.34 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochlorideand 200 μL (1.162 mmol) DIPEA were added to 100 mg (0.39 mmol)(6-chloropyrimidin-4-yl)-indol-1-yl-methanone in 30 mL DMF. The reactionmixture was stirred for 3 h at RT. The reaction mixture was evaporateddown i. vac. The residue was combined with 20 mL water and stirred for10 min. The solid was suction filtered and purified by flashchromatography. The product fractions were combined and evaporated downi. vac. The residue was triturated with diisopropylether and suctionfiltered. The solid was dried at 40° C. in the CAD.

Yield: 75 mg (44% of theoretical)

ESI-MS: m/z=440 (M+H)⁺

R_(f) 0.55 (silica gel, eluant A)

Example 641-{1-[6-(3-methyl-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

227 mg (0.78 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloridewere added to 200 mg (0.74 mmol)(6-chloropyrimidin-4-yl)-(3-methyl-indol-1-yl)-methanone and 413 μL(2.40 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirredovernight at RT and then purified by preparative HPLC. The productfractions were combined and concentrated by rotary evaporation using therotary evaporator. The residue was taken up in methanol and purifiedthrough a silica gel column. The product fractions were combined andconcentrated by rotary evaporation using the rotary evaporator.

Yield: 210 mg (63% of theoretical)

ESI-MS: m/z=454 (M+H)⁺

R_(t) (HPLC-MS): 1.46 min (method C)

Example 651-{1-[6-(5-fluoroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

75.0 mg (0.26 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochlorideand 150 μL (0.87 mmol) DIPEA were added to 70 mg (0.25 mmol)(6-chloropyrimidin-4-yl)-(5-fluoroindol-1-yl)-methanone in 5 mL DMF. Thereaction mixture was stirred overnight at RT and then evaporated down i.vac. The residue was taken up in 20 mL water and stirred for 10 min. Theprecipitate was suction filtered, dissolved in 2.5 mL DMF and purifiedby preparative HPLC. The product fractions were combined andconcentrated by rotary evaporation using the rotary evaporator.

Yield: 40 mg (34% of theoretical)

ESI-MS: m/z=458 (M+H)⁺

R_(f) (silica gel): 0.45 (eluant A)

Example 663-{1-[6-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

0.12 g (0.29 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 60 mg (0.31 mmol) 4,5-difluoroindoline-hydrochloride, 0.10 mL(0.71 mmol) TEA and 0.10 g (0.31 mmol) TBTU were stirred overnight in 10mL DMF at RT. The reaction mixture was concentrated to dryness by rotaryevaporation and then purified by HPLC. The product-containing fractionswere combined and freeze-dried.

Yield: 58 mg (38% of theory)

ESI-MS: m/z=535 (M+H)⁺

R_(f) (silica gel): 0.70 (DCM/cyclohexane/MeOH/NH4OH=70:15:15:2)

Analogously to3-{1-[6-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-onethe following compounds were prepared from in each case 0.15-0.44 mmol6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 1.0 to 1.3 eq TBTU, 1.2 to 4.2 eq TEA and 1 to 1.5 eq of therespective amine in a suitable amount of solvent such as NMP or DMF:

Structure [amount of amine] Analytical Ex. Name Amine Yield data  67

80 mg (0.38 mmol) 5-fluoro-3-(2-methoxy- ethyl)-3-methyl-2,3- dihydro-1H-indole 110 mg (49% of theory) ESI MS: m/z = 589 [M + H]⁺ R_(t) = 1.54min method C 3-(1-{6-[5-fluoro-3-(2-methoxy-ethyl)-3-methyl-2,3-dihydro-indole-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  68

45 mg (0.33 mmol) 5-fluoro-2,3-dihydro- 1H-indole 94 mg (60% of theory)ESI-MS: m/z = 517 [M + H]⁺ R_(f) = 0.75 silica gel, (eluant A3-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3- benzodiazepin-2-one 69

37 mg (0.22 mmol) 4,5-difluoro-3-methyl- 2,3-dihydro-1H-indole 70 mg(63% of theory) ESI-MS: m/z = 549 [M + H]⁺ R_(t) = 4.2 min method K3-{1-[6-(4,5-difluoro-3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  70

47 mg (0.30 mmol) 5,6-difluoro-2,3- dihydro-1 H-indole 66 mg (49% oftheory) ESI-MS: m/z = 535 [M + H]⁺ R_(t) = 1.5 min method C3-{1-[6-(5,6-difluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro- benzodiazepin-2-one  71

36 mg (0.21 mmol) 5,6-difluoro-3-methyl- 2,3-dihydro-1H-indole 45 mg(41% of theory) ESI-MS: m/z = 549 [M + H]⁺ R_(t) = 4.4 min method K3-{1-[6-(5,6-difluoro-3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  72

37 mg (0.20 mmol) 4-methyl-1,2,3,4- tetrahydro- isoquinolinehydrochloride 17 mg (18% of theory) ESI-MS: m/z = 527 [M + H]⁺ R_(t) =1.38 min method C7-methoxy-3-{1-[6-(4-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  73

25 mg (0.15 mmol) S-(-)-(1,2,3,4- tetrahydro-isoquinolin- 3-yl)-methanol42 mg (51% of theory) ESI-MS: m/z = 543 [M + H]⁺ R_(t) = 1.27 min methodC (S)-3-{1-[6-(3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  74

28 mg (0.15 mmol) 5-fluoro-1,2,3,4- tetrahydro- isoquinolinehydrochloride 12 mg (15% of theory) ESI-MS: m/z = 531 [M + H]⁺ R_(t) =1.37 min method C3-{1-[6-(5-fluoro-3,4-dihydro-1H-iso-quinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  75

28 mg (0.15 mmol) 7-fluoro-1,2,3,4- tetrahydro- isoquinolinehydrochloride 12 mg (15% of theory) ESI-MS: m/z = 531 [M + H]⁺ R_(t) =1.36 min method C3-{1-[6-(7-fluoro-3,4-dihydro-1H-iso-quinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  76

80 mg (0.44 mmol) 4,5-difluoro-3,3- dimethyl-2,3-dihydro- 1H-indole 150mg (61% of theory) ESI-MS: m/z = 563 [M + H]⁺ R_(t) = 1.63 min method C3-{1-[6-(4,5-difluoro-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  77

20 mg (0.15 mmol) 1,2,3,4-tetrahydro- isoquinoline 40 mg (52% of theory)ESI-MS: m/z = 513 [M + H]⁺ R_(t) = 1.36 min method C3-{1-[6-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  78

31 mg (0.15 mmol) 5,8-difluoro-1,2,3,4- tetrahydro- isoquinoline 47 mg(57% of theory) ESI-MS: m/z = 549 [M + H]⁺ R_(t) = 1.43 min method C3-(1-[6-(5,8-difluoro-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  79

40 mg (0.21 mmol) 7,7-dimethyl-4,5,6,7- tetrahydro-thieno-[3,2-c]pyridine 29 mg (25% of theory) ESI-MS: m/z = 547 [M + H]⁺ R_(t) =3.94 min method K3-{1-[6-(7,7-dimethyl-6.7-dihydro-4H-thieno[3,2-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  80

28 mg (0.15 mmol) 8-fluoro-1,2,3,4- tetrahydro- isoquinolinehydrochloride 22 mg (28% of theory) ESI-MS: m/z = 531 [M + H]⁺ R_(t) =1.38 min method C3-{1-[6-(8-fluoro-3,4-dihydro-1H-iso-quinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  81

40 mg (0.30 mmol) 3-methyl-2,3-dihydro- 1H-indole 85 mg (66% of theory)ESI-MS: m/z = 513 [M + H]⁺ R_(f) = 0.77 silica gel, (eluant A7-methoxy-3-{1-[6-(3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  82

25 mg (0.15 mmol) (1,2,3,4-tetrahydro- isoquinolin-4-yl)- methanol 4 mg(5% of theory) ESI-MS: m/z = 543 [M + H]⁺ R_(t) = 1.27 min method C3-{1-[6-(4-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  83

50 mg (0.35 mmol) 2,3-dihydro-1H-indole- 5-carbonitrile 30 mg (19% oftheory) ESI-MS: m/z = 524 [M + H]⁺ R_(f) = 0.77 silica gel, (eluant A1-{6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-2,3-dihydro-1H-indole-5-carbonitrile 84

32 mg (0.15 mmol) (1,2,3,4-tetrahydro- isoquinolin-1-yl)- acetonitrilehydrochloride 39 mg (47% of theory) ESI MS: m/z = 552 [M + H]⁺ R_(t) =1.39 min method C(2-{6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetonitrile  85

36 mg (0.15 mmol) 5-trifluoromethyl- 1,2,3,4-tetrahydro- isoquinolinehydrochloride 41 mg (47% of theory) ESI-MS: m/z = 581 [M + H]⁺ R_(t) =1.47 min method C7-methoxy-3-{1-[6-(5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one 86

30 mg (0.15 mmol) 5-methoxy-1,2,3,4- tetrahydro- isoquinolinehydrochloride 42 mg (51% of theory) ESI-MS: m/z = 543 [M + H]⁺ R_(t)=1.39 min method C7-methoxy-3-{1-[6-(5-methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one  87

50 mg (0.31 mmol) 2-(2,3-dihydro-1H- indol-3-yl)-ethanol 90 mg (66% oftheory) ESI-MS: m/z = 543 [M + H]⁺ R_(f) = 0.77 silica gel, eluant A3-(1-{6-[3-(2-hydroxy-ethyl)-2,3-dihydroindole-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-diazepin-2-one 88

33 mg (0.21 mmol) 5,7-difluoro-2- dihydro-1H-indole 35 mg (33% oftheory) ESI-MS: m/z = 535 [M + H]⁺ R_(t) = 4.8 min method B3-{1-[6-(5,7-difluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one  89

36 mg (0.15 mmol) 4,4-dimethyl-1-pyridin- 4-yl-1,2,3,4- tetrahydro-isoquinoline 34 mg (37% of theory) ESI-MS: m/z = 618 [M + H]⁺ R_(t) =1.51 min method C 3-{1-[6-(4,4-dimethyl-1-pyridin-4-yl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo-[d][1,3]diazepin-2-one  90

34 mg (0.23 mmol) 3-ethyl-2,3-dihydro- 1H-indole 29 mg (26% of theory)ESI-MS: m/z = 527 [M + H]⁺ R_(t) = 1.52 min method C3-{1-[6-(3-ethyl-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one  91

69 mg (0.15 mmol) 1-methyl-1,2,3,4- tetrahydro- isoquinolinehydrochloride 10 mg (13% of theory) ESI-MS: m/z = 527 [M + H]⁺ R_(t) =1.44 min method C7-methoxy-3-{1-[6-(1-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one  92

125 mg (0.34 mmol) 1,7,7-trimethyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]- pyridinium trifluoroacetate 44 mg (29% of theory)ESI-MS: m/z = 545 [M + H]⁺ R_(t) = 2.75 min method E7-methoxy-3-{1-[6-(1,7,7-trimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]-pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one  93

11 mg (0.08 mmol) 4-methyl-decahydro- quinoline 12 mg (15% of theory)ESI-MS: m/z = 533 [M + H]⁺ R_(t) = 1.45 min method C7-methoxy-3-{1-[6-(4-methyl-octahydro-quinoline-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one  94

50 mg (0.26 mmol) 3-trifluoromethyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine 65 mg (57% of theory) ESI-MS: m/z = 571 [M + H]⁺R_(t) = 2.92 min method E7-methoxy-3-{1-[6-(3-trifluoromethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one  95

0.16 g (0.24 mmol) 7,7-dimethyl-4,5,6,7- tetrahydro-thieno[3,4c]pyridine 7.4 mg (6% of theory) ESI-MS: m/z = 547 [M + H]⁺R_(t) = 4.03 min method E3-{1-[6-(7,7-dimethyl-6.7-dihydro-4H-thieno[3,4-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one  96

40 mg (0.23 mmol) 3-cyclopropyl-methyl- 2,3-dihydro-1H-indole 76 mg (66%of theory) ESI-MS: m/z = 553 [M + H]⁺ R_(t)= 1.62 min method C3-{1-[6-(3-cyclopropylmethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one 97

21 mg (0.15 mmol) 4,5,6,7-tetrahydro- thieno[2,3-c]pyridine 38 mg (49%of theory) ESI-MS: m/z = 519 [M + H]⁺ R_(t) = 1.31 min method C3-{1-[6-(4.7-dihydro-5H-thieno[2,3-c]pyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one 98

31 mg (0.15 mmol) 1-thiophen-2-yl- 1,2,3,4-tetrahydro- pyrrolo-[1,2-a]pyrazine 47 mg (53% of theory) ESI-MS: m/z = 584 [M + H]⁺ R_(t) =1.50 min method C7-methoxy-3-{1-[6-(1-thiophene-2-yl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one  99

55 mg (0.25 mmol) 2-methyl-5,6-dihydro- 4H-pyrrolo[3,4- d]thiazolehydrobromide 62 mg (53% of theory) ESI-MS: m/z = 520 [M + H]⁺ R_(t) =2.95 min method E7-methoxy-3-{1-[6-(2-methyl-4,6-dihydro-pyrrolo[3,4-d]thiazole-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one100

24 mg (0.15 mmol) 3,3-dimethyl-1,2,3,4- tetrahydro- isoquinoline 35 mg(43% of theory) ESI-MS: m/z = 541 [M + H]⁺ R_(t) = 1.57 min method C3-{1-[6-(3,3-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one101

110 mg (0.52 mmol) methyl 2,3-dihydro- 1H-indole-3- carboxylatehydrochloride 20 mg (7% of theory) ESI-MS: m/z = 557 [M + H]⁺ R_(f) =0.78 silica gel, eluant A methyl1-{6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-2,3-dihydro-1H-indole-3-carboxylate102

28 mg (0.15 mmol) 6-fluoro-1,2,3,4- tetrahydro- isoquinolinehydrochloride 41 mg (51% of theory) ESI-MS: m/z = 531 [M + H]⁺ R_(t) =1.36 min method C3-{1-[6-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one103

21 mg (0.15 mmol) 4,5,6,7-tetrahydro- thieno[3,2-c]pyridine 40 mg (51%of theory) ESI-MS: m/z = 519 [M + H]⁺ R_(t) = 1.31 min method C3-{1-[6-(6.7-dihydro-4H-thieno[3,2-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one104

21 mg (0.15 mmol) 1-methyl-1,2,3,4- tetrahydro-pyrrolo- [1,2-a]pyrazine40 mg (51% of theory) ESI-MS: m/z = 516 [M + H]⁺ R_(t) = 1.30 min methodC 7-methoxy-3-{1-[6-(1-methyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one 105

21 mg (0.15 mmol) 1-methyl-4,5,6,7- tetrahydro-1H-pyrrolo[3,2-c]pyridine 22 mg (28% of theory) ESI-MS: m/z = 516 [M + H]⁺R_(t) = 1.28 min method C7-methoxy-3-{1-[6-(1-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one 106

26 mg (0.15 mmol) 4-allyl-1,2,3,4- tetrahydro- isoquinoline 18 mg (22%of theory) ESI-MS: m/z = 553 [M + H]⁺ R_(t) = 1.63 min method C3-{1-[6-(4-allyl-3,4-dihydro-1H-iso-quinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one107

45 mg (0.23 mmol) 3-trifluoromethyl- 4,5,6,7-tetrahydro- isoxazolo-[4,3-c]pyridin 85 mg (74% of theory) ESI-MS: m/z = 572 [M + H]⁺ R_(t) = 3.45min method E 7-methoxy-3-{1-[6-(3-trifluoromethyl-6.7-dihydro-4H-isoxazolo[4,3-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one 108

41 mg (0.23 mmol) 3-(2-methoxy-ethyl)- 2,3-dihydro-1H-indole 83 mg (71%of theory) ESI-MS: m/z = 557 [M + H]⁺ R_(t) = 3.94 min method E7-methoxy-3-(1-{6-[3-(2-methoxy-ethyl)-2,3-dihydro-indole-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one109

29 mg (0.15 mmol) 3-methyl-decahydro- quinoline hydrochloride 13 mg (16%of theory) ESI-MS: m/z = 533 [M + H]⁺ R_(t) = 1.48 min method C7-methoxy-3-{1-[6-(3-methyl-octahydro-quinoline-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one 110

30 mg (0.15 mmol) 7-methoxy-1,2,3,4- tetrahydro-iso- quinolinehydrochloride 42 mg (51% of theory) ESI-MS: m/z = 543 [M + H]⁺ R_(t) =1.36 min method C7-methoxy-3-{1-[6-(7-methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one111

60 mg (0.31 mmol) 4,5,6,7-tetrahydro-1H- imidazo[4,5-c]pyridinedihydro-chloride 32 mg (32% of theory) ESI-MS: m/z = 503 [M + H]⁺ R_(t)= 2.05 min method E7-methoxy-3-{1-[6-(1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one112

36 mg (0.15 mmol) 8-trifluoromethyl- 1,2,3,4-tetrahydro- isoquinolinehydrochloride 42 mg (48% of theory) ESI-MS: m/z = 581 [M + H]⁺ R_(t)=1.45 min method C7-methoxy-3-{1-[6-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one 113

69 mg (0.43 mmol) 4,4-dimethyl-1,2,3,4- tetrahydro-quinoline 0.12 g (59%of theory) ESI-MS: m/z = 541 [M + H]⁺ R_(t) = 3.75 min method K3-{1-[6-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one 114

75 mg (0.31 mmol) 4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridinedihydrochloride dimethylether 40 mg (40% of theory) ESI-MS: m/z = 503[M + H]⁺ R_(t) = 2.24 min method E7-methoxy-3-{1-[6-(1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one 115

50 mg (0.28 mmol) 1,4,5,6-tetrahydro- pyrrolo[3,4-c]pyrazoledihydrochloride 63 mg (64% of theory) ESI-MS: m/z = 489 [M + H]⁺ R_(t) =2.4 min method E3-{1-[6-(4,6-dihydro-1H-pyrrolo[3.4c]-pyrazole-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetra-hydrobenzo[d]-[1,3]diazepin-2-one116

60 mg (0.37 mmol) 5,6,7,8-tetrahydro- [1,2,4]-triazolo[4.3a]- pyrazinehydrochloride 23 mg (23% of theory) ESI-MS: m/z = 504 [M + H]⁺ R_(t) =2.3 min method E3-{1-[6-(5,6-dihydro-8H-[1,2,4]-triazolo[4,3-a]pyrazin-7-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetra-hydrobenzo[d]-[1,3]diazepin-2-one117

26 mg (0.15 mmol) 2-methyl-4,5,6,7-tetra- hydro-1H-imidazo[4,5-c]pyridine hydrochloride 27 mg (35% of theory) ESI-MS: m/z = 517 [M +H]⁺ R_(t) = 1.19 min method C7-methoxy-3-{1-[6-(2-methyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetra-hydrobenzo[d]-[1,3]diazepin-2-one

Example 1184′-(4,5-difluoro-2,3-dihydroindole-1-carbonyl)-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d]-[1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile

0.10 g (0.24 mmol)5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylicacid, 45 mg (0.24 mmol) 4,5-difluoro-2,3-dihydro-1H-indole hydrochlorideand 0.103 mL (0.74 mmol) TEA were placed in 2 mL DMF. 83.8 mg (0.26mmol) TBTU were added, the reaction mixture was stirred overnight at RTand then purified by HPLC. The product-containing fractions werecombined and freeze-dried.

Yield: 24 mg (18% of theory)

ESI-MS: m/z=559 (M+H)⁺

R_(t) (HPLC-MS): 3.23 min (method O)

Example 1194′-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile

100 mg (0.24 mmol)5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid, 53.2 mg (0.24 mmol)7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinedihydrochloride, 137 μL (0.97 mmol) TEA and 83.8 mg (0.26 mmol) TBTUwere stirred in 2 mL DMF overnight at RT. The reaction mixture waspurified by HPLC. The product-containing fractions were combined andfreeze-dried.

Yield: 19 mg (14% of theory)

ESI-MS: m/z=555 (M+H)⁺

R_(t) (HPLC-MS): 1.29 min (method C)

Example 1203-[4′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

633 mg (2.3 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,700 mg (2.28 mmol)(2-chloro-6-methoxy-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanoneand 953.6 mg (6.9 mmol) potassium carbonate were stirred in 5 mL of NMPfor 8 h at 130° C. The undissolved solid was filtered off and thefiltrate was purified by HPLC. The product-containing fractions werecombined and concentrated to dryness by rotary evaporation. For furtherpurification the residue was combined with DMF and the undissolved solidwas suction filtered and dried.

Yield: 490 mg (39% of theory)

ESI-MS: m/z=547 (M+H)⁺

R_(t) (HPLC-MS): 1.5 min (method C)

Example 1213-[2′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

0.18 g (0.67 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,0.20 g (0.68 mmol)(4-chloro-pyridin-2-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanoneand 97 mg (0.70 mmol) potassium carbonate were stirred in 3 mL of NMPfor 4 h at 130° C. and overnight at RT. The reaction mixture waspurified by HPLC. The product-containing fractions were combined andfreeze-dried.

Yield: 55 mg (15% of theory)

ESI-MS: m/z=534 (M+H)⁺

R_(t) (HPLC-MS): 1.40 min (method C)

Example 1227-methoxy-3-{1-[6-(octahydro-indol-1-carbonyl)-pyrimidin-4-yl]piperidin-4-yl}-1,3,4,5-tetra-hydro-1,3-benzodiazepin-2-one

705 mg (2.56 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,680 mg (2.56 mmol)(6-chloro-pyrimidin-4-yl)-(octahydro-indol-1-yl)-methanone and 0.871 mL(5 mmol) DIPEA were stirred in 10 mL DMF for 2 h at RT. The reactionmixture was purified by HPLC. The product-containing fractions werecombined and the ACN was eliminated by rotary evaporation. The aqueousphase was made alkaline with 4M NaOH and extracted with EtOAc. Theorganic phase was dried, filtered and the filtrate was concentrated todryness by rotary evaporation. The residue was crystallised from amixture of MeOH and diethyl ether and the solid was suction filtered anddried.

Yield: 520 mg (40% of theory)

ESI-MS: m/z=505 (M+H)⁺

R_(t) (HPLC-MS): 3.28 min (method E)

Example 1233-{1-[4-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-[1,3,5]triazin-2-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

0.11 g (0.26 mmol)4-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylicacid, 59 mg (0.26 mmol)7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinedihydrochloride and 0.15 mL (1.1 mmol) TEA were placed in 1.5 mL DMF. 93mg (0.29 mmol) TBTU were added and the reaction mixture was stirred forthree days at RT. The substance was purified by HPLC-MS. Theproduct-containing fractions were combined and freeze-dried.

Yield: 8 mg (6% of theory)

ESI-MS: m/z=532 (M+H)⁺

R_(t) (HPLC-MS): 3.11 min (method E)

Example 1243-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5-methyl-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

70 mg (0.17 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidine-4-carboxylicacid, 26.1 mg (0.19 mmol) 5-fluoroindoline, 61 mg (0.19 mmol) TBTU and0.027 mL (0.19 mmol) TEA were stirred in 1 mL DMF for 3 h at RT. Thereaction mixture was purified by HPLC-MS. The product-containingfractions were combined and freeze-dried.

Yield: 58 mg (6% of theory)

ESI-MS: m/z=531 (M+H)⁺

R_(t) (HPLC-MS): 1.45 min (method C)

Example 1254′-(2,3-dihydro-indole-1-carbonyl)-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzo-diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile

0.02 g (0.48 mmol)5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid, 57 mg (0.48 mmol) 2,3-dihydro-1H-indole and 0.21 mL (1.5 mmol) TEAwere placed in 3 mL DMF. 0.17 g (0.52 mmol) TBTU were added. Thereaction mixture was stirred overnight at RT and then purified by HPLC.The product-containing fractions were combined and freeze-dried.

Yield: 38 mg (15% of theory)

ESI-MS: m/z=523 (M+H)⁺

R_(t) (HPLC-MS): 1.53 min (method C)

Example 1263-[4′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

0.18 g (0.67 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,0.020 g (0.68 mmol)(2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanoneand 97 mg (0.70 mmol) potassium carbonate were stirred in 3 mL NMP for 4h at 130° C., then overnight at RT. The reaction mixture was purified byHPLC. The product-containing fractions were combined and freeze-dried.

Yield: 42 mg (12% of theory)

ESI-MS: m/z=534 (M+H)⁺

R_(t) (HPLC-MS): 1.4 min (method C)

Example 1273-{1-[6-(hexahydro-cyclopenta[c]pyrrol-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

80 mg (0.20 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 40 mg (0.27 mmol) octahydrocyclopenta[c]pyrrole hydrochloride,0.080 mL (0.57 mmol) TEA and 80 mg (0.25 mmol) TBTU were stirred in 0.9mL DMF overnight at RT. The reaction mixture was combined with saturatedsodium hydrogen carbonate solution and ice water, and the precipitatedsolid was suction filtered and dried.

Yield: 74 mg (75% of theory)

ESI-MS: m/z=491 (M+H)⁺

R_(t) (HPLC-MS): 3.14 min (method E)

Example 1283-{1-[6-(4,4-dimethyl-4.7-dihydro-5H-thieno[2,3-c]pyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

84 mg (0.21 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 40 mg (0.24 mmol)4,4-dimethyl-4,5,6,7-tetra-hydro-thieno[2,3-c]pyridine, 34 μL (0.24mmol) TEA and 77 mg (0.24 mmol) TBTU were stirred in 1 mL DMF overnightat RT. The reaction mixture was purified by HPLC. The product-containingfractions were combined and freeze-dried.

Yield: 62 mg (54% of theory)

ESI-MS: m/z=547 (M+H)⁺

R_(t) (HPLC-MS): 3.57 min (method E)

Example 1293-{1-[6-(6-fluoro-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

60 mg (0.15 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 33 mg (0.15 mmol)6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride, 66μL (0.47 mmol) TEA and 54 mg (0.17 mmol) TBTU were stirred in 1.5 mL DMFovernight at RT. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 22 mg (26% of theory)

ESI-MS: m/z=559 (M+H)⁺

R_(t) (HPLC-MS): 1.49 min (method C)

Example 1303-{1-[6-(5-fluoro-3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

80 mg (0.21 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 32 mg (0.21 mmol) 5-fluoro-3-methyl-2,3-dihydro-1H-indole, 70 μL(0.50 mmol) TEA and 74 mg (0.23 mmol) TBTU were stirred in 1.8 mL DMFovernight at RT. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 64 mg (60% of theory)

ESI-MS: m/z=531 (M+H)⁺

R_(t) (HPLC-MS): 3.8 min (method K)

Example 1313-{1-[6-(4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

0.10 g mg (0.25 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 57 mg (0.35 mmol) 4,4-dimethyl-1,2,3,4-tetra-hydro-isoquinoline,75 μL (0.53 mmol) TEA and 0.11 (0.30 mmol) TBTU were stirred in 1.1 mLDMF overnight at RT. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 81 mg (60% of theory)

ESI-MS: m/z=541 (M+H)⁺

R_(t) (HPLC-MS): 3.59 min (method E)

Example 1323-(1-(6-(2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinolin]-2′-ylcarbonyl)pyrimidin-4-yl)-piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one

50 mg (0.13 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 20 mg (0.13 mmol)2′,3′-dihydro-1′H-spiro-[cyclopropane-1,4′-isoquinoline], 37 μL (0.26mmol) TEA and 44.3 mg (0.14 mmol) TBTU were stirred in 1.5 mL DMFovernight at RT. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 5 mg (7% of theory)

ESI-MS: m/z=539 (M+H)⁺

R_(t) (HPLC-MS): 3.98 min (method E)

Example 1331-{1-[6-(4,5-difluoro-3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

80 mg (0.24 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 43 mg (0.25 mmol) 4,5-difluoro-3-methyl-2,3-dihydro-1H-indole, 70μL (0.50 mmol) TEA and 90 mg (0.28 mmol) TBTU were stirred in 1.8 mL DMFovernight at RT. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 76 mg (66% of theory)

ESI-MS: m/z=492 (M+H)⁺

R_(t) (HPLC-MS): 3.6 min (method K)

Analogously to1-{1-[6-(4,5-difluoro-3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-onethe following compounds were prepared from in each case 0.24-0.43mmol-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]pyrimidine-4-carboxylicacid, 1 to 1.5 eq of the respective amine, 1.0 to 1.2 eq TBTU and 1.1 to4.1 eq triethylamine in a suitable amount of DMF:

[Amount of amine] Structure Amine Analytical Ex. Name Yield data 134

 1-{1-[6-(5,6-difluoro-3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one 40 mg (0.24mmol) 5,6-difluoro-3- methyl-2,3-dihydro- 1H-indole 70 mg (61% oftheory) ESI-MS: m/z = 492 [M + H]⁺ R_(t) = 3.8 min method K 135

  1-{1-[6-(5,6-difluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 62 mg (0.40mmol) 5,6-difluoro-2,3- dihydro-1H-indole 72 mg (51% of theory) ESI-MS:m/z = 478 [M + H]⁺ 1.4 min method C 136

  1-(1-{6-[5-fluoro-3-(2-methoxy-ethyl)-3-methyl-2,3-dihydro-indole-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 80 mg (0.38mmol) 5-fluoro-3-(2- methoxy-ethyl)-3- methyl-2,3-dihydro- 1H-indole 83mg (41% of theory) ESI-MS: m/z = 530 [M + H]⁺ 1.4 min method C 137

  1-{1-[6-(4,5-difluoro-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydroimidazo[4,5-b]pyridin-2-one 80 mg (0.44 mmol)4,5-difluoro-3,3- dimethyl-2,3- dihydro-1H-indole 0.10 g (45% of theory)ESI-MS: m/z = 506 [M + H]⁺ 1.4 min method C 138

  1-{1-[6-(4-fluoro-2,3-dihydroindole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 45 mg (0.33mmol) 4-fluoro-2,3-dihydro- 1H-indole 95 mg (70% of theory) ESI-MS: m/z= 460 [M + H]⁺ R_(f) = 0.63 silica gel, eluant A) 139

  1-{1-[6-(octahydro-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 50 mg (0.36mmol) decahydro- isoquinoline 33 mg (23% of theory) ESI-MS: m/z = 462[M + H]⁺ 3.03 min method E 140

 1-{1-[6-(7,7-dimethyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one40 mg (0.24 mmol) 7,7-dimethyl-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine 12 mg (12% of theory) ESI-MS: m/z = 490 [M + H]⁺3.42 min method K 141

  1-{1-[6-(4-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 50 mg (0.30mmol) 4-methyl-2,3- dihydro-1H-indole hydrochloride 95 mg (71% oftheory) ESI-MS: m/z = 456 [M + H]⁺ R_(f) = 0.67 silica gel, eluant A 142

  1-{1-[6-(3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 40 mg (0.30mmol) 3-methyl-2,3- dihydro-1H-indole 65 mg (54% of theory) ESI-MS: m/z= 456 [M + H]⁺ R_(f) = 0.62 silica gel, eluant A) 143

 1-{1-[6-(6-fluoro-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidn-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one38 mg (0.18 mmol) 6-fluoro-4,4- dimethyl-1,2,3,4- tetrahydro-isoquinoline hydrochloride 5 mg (6% of theory) ESI-MS: m/z = 502 [M +H]⁺ 1.34 min method C 144

  1-{1-[6-(6-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 45 mg (0.33mmol) 6-fluoro-2,3-dihydro- 1H-indole 0.10 g (74% of theory) ESI-MS: m/z= 460 [M + H]⁺ R_(f) = 0.71 silica gel, eluant A 145

  1-{1-[6-(5-methoxy-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 60 mg (0.32mmol) 5-methoxy-2,3- dihydro-1H-indole hydrochloride 95 mg (69% oftheory) ESI-MS: m/z = 470 [M + H]⁺ R_(f) = 0.64 silica gel, eluant A 146

  1-{1-[6-(4,4-dimethyl-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-carbonyl)-pyrimidn-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one40 mg (0.24 mmol) 4,4-dimethyl-4,5,6,7- tetrahydro- thieno[2,3-c]pyrdine31 mg (30% of theory) ESI-MS: m/z 490 [M + H]⁺ 3.03 min method E 147

 1-{1-[6-(4-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 42 mg (0.23mmol) 4-methyl-1,2,3,4- tetra- hydroisoqinoline hydrochloride 25 mg (26%of theory) ESI-MS: m/z = 578 [M + H]⁺ 3.9 min method B 148

  1-{1-[6-(5,7-difluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperdin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 37 mg (0.2 mmol)4-methyl-1,2,3,4- tetrahydro- isoquinoline 48 mg (43% of theory) ESI-MS:m/z = 470 [M + H]⁺ 1.2 min method C 149

  1-{1-[6-(3-ethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 34 mg (0.23mmol) 3-ethyl-2,3-dihydro- 1H-indole 22 mg (23% of theory) ESI-MS: m/z =470 [M + H]⁺ 1.6 min method C 150

  1-{1-[6-(3-cyclopropylmethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one40 mg (0.23 mmol) 3-cyclopropyl- methyl-2,3-dihydro- 1H-indole 45 mg(44% of theory) ESI-MS: m/z = 496 [M + H]⁺ 1.47 min (method C) 151

  methyl1-{6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-2,3-dihydro-1H-indole-3-carboxylate 130 mg(0.61 mmol) methyl 2,3-dihydro- 1H-indole-3- carboxylate hydrochloride160 mg (55% of theory) ESI-MS: m/z = 500 [M + H]⁺ R_(f) = 0.64 silicagel, eluant A 152

  1-(1-{6-[3-(2-methoxy-ethyl)-2,3-dihydro-indole-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 41 mg(0.23 mmol) 2-(2-methoxy-ethyl)- 2,3-dihydro-1H- indole 72 mg (70% oftheory) ESI-MS: m/z = 500 [M + H]⁺ 3.33 min method E 153

  1-{1-[6-(2-allyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 60 mg (0.31mmol) 2-allyl-2,3-dihydro- 1H-indole hydrochloride 72 mg (51% of theory)ESI-MS: m/z = 482 [M + H]⁺ R_(f) = 0.62 silica gel, eluant A 154

  1-{1-[6-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 81 mg (0.5mmol) 4,4-dimethyl-1,2,3,4- tetrahydro-quinoline 118 mg (55% of theory)ESI-MS: m/z = 484 [M + H]⁺ 3.17 min (method K) 155

  1-(1-(6-(1-methylspiro[indolin-3,4′-piperidin]-1-ylcarbonyl)-pyrimidin-4-yl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one 62 mg(0.3 mmol) 1′- methylspiro[indoline- 3,4′-piperidine] 118 mg (77% oftheory) ESI-MS: m/z = 525 [M + H]⁺ 2.2 min (method K) 156

  1-(1-{6-[3-(2-hydroxy-ethyl)-2,3-dihydro-indole-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 50 mg(0.31 mmol) 2-(2,3-dihydro-1H- indol-3-yl)-ethanol 85 mg (66% of theory)ESI-MS: m/z = 486 [M + H]⁺ R_(f) = 0.59 silica gel, eluant A 157

  1-{1-[6-(2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 45 mg(0.32 mmol) 2,3-dihydro-1H- pyrrolo[2,3- b]pyridine 50 mg (39% oftheory) ESI-MS: m/z = 443 [M + H]⁺ R_(f) = 0.54 silica gel, eluant A 158

  1-{1-[6-(2-phenyl-pyrrolidine-1-carbonyl)-pyrimidin-4-yl]-piperidine-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 45 mg (0.31mmol) 2-phenylpyrrolidine 65 mg (47% of theory) ESI-MS: m/z = 470 [M +H]⁺ R_(f) = 0.61 silica gel, eluant A 159

  6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid (2-phenyl-butyl)-amide 46 mg (0.31 mmol)2-phenylbutan-1- amine 80 mg (58% of theory) ESI-MS: m/z = 472 [M + H]⁺R_(f) = 0.56 silica gel, eluant A 160

  1-{1-[6-(3-pyridin-4-yl-pyrrolidine-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 45 mg (0.3 mmol)4-pyrrolinin-3- ylpyridine 20 mg (15% of theory) ESI-MS: m/z = 471 [M +H]⁺ R_(f) = 0.55 silica gel, eluant A 161

  6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-caboxylic acid (2-phenyl-propyl)-amide 40 mg (0.3 mmol)Beta-methyl- phenethylamine 72 mg (54% of theory) ESI-MS: m/z = 458 [M +H]⁺ R_(f) = 0.62 silica gel, eluant A

Example 1621-{1-[2-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

60 mg (0.18 mmol)4-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylicacid, 40 mg (0.18 mmol)7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinedihydrochloride, 0.10 (0.72 mmol) triethylamine and 62 (0.19 mmol) TBTUin 1.5 mL DMF were stirred overnight at RT. The reaction mixture waspurified by HPLC. The product-containing fractions were combined andfreeze-dried.

Yield: 25 mg (30% of theory)

ESI-MS: m/z=474 (M+H)⁺

R_(t) (HPLC-MS): 0.91 min (method C)

Example 1631-[4′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

0.59 g (2.7 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.80 g (2.7mmol)(2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanoneand 0.39 g (2.8 mmol) potassium carbonate were stirred in 3 mL of NMPfor 4 h at 130° C. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 74 mg (6% of theory)

ESI-MS: m/z=477 (M+H)⁺

R_(t) (HPLC-MS): 1.26 min (method C)

Example 1641-[4′-(5,6-difluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

1.0 g (4.6 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.45 g (1.5mmol)(2-chloro-pyridin-4-yl)-(5,6-difluoro-2,3-dihydro-indol-1-yl)-methanonewere stirred in 4 mL of NMP for 4 h at 130° C. The reaction mixture waspurified by HPLC. The product-containing fractions were combined andfreeze-dried.

Yield: 46 mg (2% of theory)

ESI-MS: m/z=477 (M+H)⁺

R_(t) (HPLC-MS): 3.4 min (method E)

The following compounds were synthesised according to the followingGeneral Working Method:

0.4 to 1 mmol 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-onedihydrochloride, 1 eq of the respective chloropyridine and 3 eqpotassium carbonate in 1 to 3 mL NMP were stirred for 4 to 12 h at 130°C. Purification was carried out by HPLC. Instead of the1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloridethe free base was used, so only 1 eq potassium carbonate was used:

[Amount of pyridine] Structure Amine Analytical Example Name Yield data165

  1-[4′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-1′-oxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 140 mg (0.48 mmol) (2-chloro-1-oxy-pyridin-4-yl)-(5-fluoro- 2,3-dihydro-indol-1-y1)- methanone 70 mg (30%of theory) ESI-MS: m/z = 475 [M + H]⁺ 3.84 min (method K) 166

  1-[2'-(5-fluoro-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 120 mg (0.39 mmol)(4-chloro-pyridin-2-yl)- (5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)- methanone 80 mg (41% of theory) ESI-MS: m/z =487 [M + H]⁺ 1.29 min (method C) 167

  1-[2′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 200 mg (0.68 mmol)(4-chloro-pyridin-2-yl)- (4,5-difluoro-2,3- dihydro-indol-1-yl)-methanone 111 mg (35% of theory) ESI-MS: m/z = 475 [M − H]⁻ 1.23 min(method C) 168

  1-[4′-(5-fluoro-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 120 mg (0.4 mmol)(2-chloro-pyridin-4-yl)- (5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)- methanone 42 mg (22% of theory) ESI-MS: m/z =487 [M + H]⁺ 1.25 min (method C) 169

  1-[4′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 300 mg (0.98 mmol)(2-chloro-6-methoxy- pyridin-4-yl)-(5-fluoro- 2,3-dihydro-indol-1-yl)-methanone 33 mg (7% of theory) ESI-MS: m/z = 489 [M + H]⁺ 1.5 min(method C) 170

  N-[4′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-methanesulphonamide 340 mg (0.92mmol) N-[6-chloro-4-(5- fluoro-2,3-dihydro- indole-1-carbonyl)-pyridin-2-yl]- methanesulphonamide 30 mg (6% of theory) ESI-MS: m/z =552 [M + H]⁺ 1.22 min (method C)

Example 1711-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrazin-2-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

0.10 g (0.34 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride,0.11 g (0.34 mmol)(6-chloro-pyrazin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and0.20 mL (1.1 mmol) DIPEA were stirred in 1.0 mL DMF overnight at 80° C.10 mL water were added to the reaction solution, the precipitate formedwas suction filtered. The precipitate was stirred into methanol, suctionfiltered and dried.

Yield: 74 mg (6% of theory)

ESI-MS: m/z=477 (M+H)⁺

R_(t) (HPLC-MS): 1.26 min (method C)

Example 1726′-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-(2-oxo-2,3-di-hydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile

0.11 mg (0.29 mmol) of an isomer mixture of5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid and5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylicacid, 65 mg (0.29 mmol)7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinedihydrochloride and 0.17 mL (1.2 mmol) TEA were placed in 1.5 mL DMF.0.10 g (0.32 mmol) TBTU were added. The reaction mixture was stirredover the weekend at RT. The purification and separation of the isomerswere carried out by HPLC-MS. The product-containing fractions werecombined and freeze-dried.

Yield: 23 mg (16% of theory)

ESI-MS: m/z=498 (M+H)⁺

R_(t) (HPLC-MS): 3.33 min (method B)

The following was obtained as the second product:

Example 1734′-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-(2-oxo-2,3-di-hydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile

The compound was obtained as described for6-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile.

Yield: 16 mg (11% of theory)

ESI-MS: m/z=498 (M+H)⁺

R_(t) (HPLC-MS): 3.67 min (method B)

Example 1746′-(2,3-dihydro-indole-1-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile

0.11 mg (0.29 mmol) of an isomer mixture of5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid and5′-cyano-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylicacid, 34 mg (0.29 mmol) 2,3-dihydro-1H-indole and 90 μL (0.61 mmol) TEAwere placed in 1.5 mL DMF. 0.10 g (0.32 mmol) TBTU were added. Thereaction mixture was stirred over the weekend at RT. The purificationand separation of the isomers were carried out by HPLC-MS. Theproduct-containing fractions were combined and freeze-dried.

Yield: 18 mg (13% of theory)

ESI-MS: m/z=466 (M+H)⁺

R_(t) (HPLC-MS): 3.67 min (method E)

The following was obtained as the second product:

Example 1754′-(2,3-dihydro-indole-1-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]-pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile

This compound was obtained as described for6′-(2,3-dihydro-indole-1-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile.

Yield: 5 mg (4% of theory)

ESI-MS: m/z=466 (M+H)⁺

R_(t) (HPLC-MS): 3.77 min (method E)

Example 1761-{4′-[3-(2-methoxy-ethyl)-2,3-dihydro-indole-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

60 mg (0.18 mmol)4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid, 36 mg (0.2 mmol) 3-(2-methoxy-ethyl)-2,3-dihydro-1H-indole and 28μL (0.2 mmol) TEA were placed in 1 mL DMF. 64 mg (0.2 mmol) TBTU wereadded and the reaction mixture was stirred for 3 h at RT. The reactionmixture was purified by HPLC. The product-containing fractions werecombined and freeze-dried.

Yield: 35 mg (40% of theory)

ESI-MS: m/z=499 (M+H)⁺

R_(t) (HPLC-MS): 1.24 min (method C)

Analogously to1-{4′-[3-(2-methoxy-ethyl)-2,3-dihydro-indole-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-onethe following compounds were prepared from in each case 0.18 mmol4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid, 1.1 eq triethylamine, 1.1 eq TBTU and 1 equivalent of therespective amine in 1 mL DMF:

[Amount of amine] Structure Amine Analytical Ex. Name Yield data 177

  1-[4′-(3-ethyl-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one 29 mg(0.2 mmol) 3-ethyl-2,3- dihydro-1H-indole 6 mg (7% of theory) ESI-MS:m/z = 469 [M + H]⁺ R_(t) = 1.34 min (method C) 178

 1-[4′-(3-cyclopropylmethyl-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo-[4.5b]pyridin-2-one 35 mg(0.2 mmol) 3-cyclopropyl- methyl-2,3-dihydro- 1H-indole 40 mg (46% oftheory) ESI-MS: m/z = 495 [M + H]⁺ R_(t)= 1.43 min (method C)

Example 1792-{1-[6-(2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,4-dihydro-2H-isoquinolin-3-one

0.10 g (0.39 mmol)(6-chloro-pyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 100 μL(0.58 mmol) DIPEA were placed in 10 mL DMF. 95 mg (0.41 mmol)2-piperidin-4-yl-1,4-dihydro-2H-isoquinolin-3-one were added. Thereaction mixture was stirred for 2 h at RT. Then the reaction mixturewas mixed with water and stirred again. The precipitated solid wassuction filtered, washed with methanol and dried.

Yield: 125 mg (72% of theory)

ESI-MS: m/z=454 (M+H)⁺

R_(f): 0.67 (silica gel, DCM/cyclohexane/MeOH/NH₄OH 70:15:15:2)

Example 1803-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-one

80 mg (0.23 mmol)6-[4-(2-oxo-1,2-dihydroquinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 35 mg (0.26 mmol) 5-fluoro-2,2-dihydro-(1H)-indole, 70 μL (0.5mmol) and 90 mg (0.28 mmol) TBTU were stirred in 3 mL DMF overnight atRT. The reaction mixture was purified by HPLC. The product-containingfractions were combined and freeze-dried.

Yield: 30 mg (28% of theory)

ESI-MS: m/z=470 (M+H)⁺

R_(t) (HPLC-MS): 1.49 min (method C)

Analogously to3-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-onethe following compounds were prepared from in each case 0.23 mmol6-[4-(2-oxo-1,2-dihydro-quinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 2.2 to 3.1 eq triethylamine, 1.2 eq TBTU and 1.1 equivalents ofthe respective amine in 3 mL DMF:

[Amount of amine] Structure Amine Analytical Example Name Yield data 181

  3-{1-[6-(4-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-one 35 mg (0.26 mmol)4-fluoro-2,3-dihydro-1H- indole 15 mg (14% of theory) ESI-MS: m/z = 470[M + H]⁺ R_(t) = 1.5 min (method C) 182

  3-{1-[6-(3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-one 35 mg (0.26 mmol)3-methyl-2,3- dihydroindole 35 mg (33% of theory) ESI-MS: m/z = 466 [M +H]⁺ R_(t) = 1.51 min (method C) 183

  3-{1-[6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-one 60 mg (0.26mmol) 5,6,7,8-tetrahydro-4H- thieno[2,3-d]-azepine hydrobromide 5 mg (5%of theory) ESI-MS: m/z = 486 [M + H]⁺ R_(t) = 1.42 min (method C) 184

  3-{1-[6-(2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-one 28 μL (0.25 mmol) indoline 35 mg (34%of theory) ESI-MS: m/z = 452 [M + H]⁺ R_(t) = 1.45 min (method C) 185

  3-{1-[6-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-one 50 mg (0.26 mmol)4,5-difluoroindoline hydrochloride 13 mg (12% of theory) ESI-MS: m/z =488 [M +H]⁺ R_(t) = 1.54 min (method C) 186:

  3-{1-[6-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1H-quinolin-2-one 55 mg (0.26 mmol)7,7-dimethyl-4,5,6,7- tetrahydro-1H- pyrazolo[4,3-c]-pyridinedihydrochloride 2 mg (2% of theory) ESI-MS: m/z = 484 [M + H]⁺ R_(t) =1.16 min (method C) 187

  3-{1-[6-(4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1 H-quinolin-2-one 50 mg (0.25mmol) 4,4-dimethyl-1,2,3,4- tetrahydro-isoquinoline hydrochloride 23 mg(20% of theory) ESI-MS: m/z = 494 [M + H]⁺ R_(t) = 1.5 min (method C)

Example 1881-{1-[6-(5-fluoro-3-methyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

80 mg (0.24 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 36 mg (0.24 mmol) 5-fluoro-3-methyl-2,3-dihydro-1H-indole, 70 μL(0.5 mmol) TEA and 90 mg (0.28 mmol) TBTU were stirred in 1.8 mL DMFovernight at RT. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 75 mg (67% of theory)

ESI-MS: m/z=474 (M+H)⁺

R_(t) (HPLC-MS): 3.2 min (method K)

Example 1896-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid-[2-(2-fluoro-phenyl)-ethyl]-amide

0.10 mg (0.29 mmol)6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 40 μL (0.31 mmol) 2-fluorophenethylamine, 45 μL (0.32 mmol) TEAand 100 mg (3.1 mmol) TBTU were stirred in 10 mL DMF overnight at RT.The reaction mixture was purified by HPLC. The product-containingfractions were combined and freeze-dried.

Yield: 70 mg (52% of theory)

ESI-MS: m/z=462 (M+H)⁺

R_(f): 0.73 (silica gel, DCM/cyclohexane/MeOH/NH₄OH 70:15:15:2)

Example 1901-[4′-(5-fluoro-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

0.26 g (0.9 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride,0.30 g (0.9 mmol)(2-chloro-6-methoxy-pyridin-4-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-methanoneand 0.37 g (2.7 mmol) potassium carbonate were stirred in 3 mL NMP for12 h at 130° C. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and freeze-dried.

Yield: 40 mg (9% of theory)

ESI-MS: m/z=517 (M+H)⁺

R_(t) (HPLC-MS): 1.62 min (method C)

Example 1911-[6′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

436 mg (2.00 mmol)1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 200 mg(0.652 mmol)(4-chloro-6-methoxy-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanonewere stirred in 2 mL NMP overnight at 120° C. The reaction mixture waspurified by preparative HPLC. The product-containing fractions werecombined and evaporated down using the rotary evaporator.

Yield: 62 mg (20% of theory)

ESI-MS: m/z=487 (M−H)⁻

R_(t) (HPLC): 1.7 min (method C)

Example 192N-[4′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-N-methyl-methanesulphonamide

0.25 g (0.89 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride,0.34 g (0.89 mmol)N-[6-chloro-4-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyridin-2-yl]-N-methyl-methanesulphonamideand 0.37 g (2.7 mmol) potassium carbonate were stirred in 3 mL of NMPfor 4 h at 130° C. The reaction mixture was purified by HPLC. Theproduct-containing fractions were combined and acetonitrile waseliminated by rotary evaporation. The precipitated substance was suctionfiltered and dried.

Yield: 160 mg (32% of theory)

ESI-MS: m/z=566 (M+H)⁺

R_(t) (HPLC-MS): 1.4 min (method C)

Example 1931-[4′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

0.98 g (4.5 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.50 g (1.5mmol)(2-chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanonewere stirred in 3 mL NMP for 12 h at 130° C. The reaction mixture waspurified by HPLC. The product-containing fractions were combined andfreeze-dried.

Yield: 0.25 g (32% of theory)

ESI-MS: m/z=507 (M+H)⁺

R_(t) (HPLC-MS): 1.59 min (method C)

Example 1943-(1-(6-((4aR,8aS)-decahydroisoquinoline-2-carbonyl)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one

1.7 mg (12 μmol) (4aR,8aS)-decahydroisoquinoline and 1.6 mg (12 μmol)DIPEA were placed in 350 μL DMF. 4.0 mg (10 μmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 10 μmol DIPEA in 100 μL DMF were activated with 3.5 mg (11μmol) TBTU in 50 μL DMF and then added dropwise. The reaction mixturewas stirred overnight and then combined with 15 μL of an aqueous 2Mpotassium carbonate solution. After 1 h stirring the precipitate formedwas allowed to settle. The supernatant solution was pipetted off andconcentrated to dryness by rotary evaporation.

Yield: 5.1 mg

ESI-MS: m/z=519 (M+H)⁺

Analogously todecahydroisoquinoline-2-carbonyl)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-onethe following compounds were prepared from 4.0 mg (10 μmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 3.6 mg (11 μmol) TBTU, 12 μmol of the corresponding amine and 3.9μL DIPEA in 350 μL DMF:

Amine Analytical Example Structure Yield data 195

 3-(1-(6-((4aS,8aS)-decahydro-isoquinoline-2-carbonyl)-pyrimidin-4-yl)-piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]-diazepin-2(3H)-one(4aS,8aS)-decahydro- isoquinoline 5 mg ESI-MS: m/z = 519 [M + H]⁺ 196

 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid (2-oxo-1.2.5,6,7,8-hexahydro-quinolin-5-yl)-amide5-amino-5,6,7,8-tetra- hydro-1H-quinolin-2- one-dihydrochloride 1.3 mgESI-MS: m/z = 544 [M + H]⁺ 197

 3-{1-[6-(6.7-dihydro-4H-thieno-[3,2-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine 5.2 mg ESI-MS: m/z = 519 [M + H]⁺ 198

 7-methoxy-3-{1-[6-(4,5,7,8-tetra-hydro-thieno[2,3-d]azepine-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one5,6,7,8-tetrahydro-4H- thieno[2,3-d] azepine 6 mg ESI-MS: m/z = 533 [M +H]⁺ 199

 7-methoxy-3-{1-[6-(octahydro-isoquinoline-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one decahydro- isoquiniline5 mg ESI-MS: m/z = 519 [M + H]⁺ 200

 7-methoxy-3-{1-[6-(1,2,4,5-tetra-hydro-benzo[d]azepine-3-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one2.3.4,5-tetrahydro-2H- benzo[d]azepine 3.1 mg ESI-MS: m/z = 527 [M + H]⁺

Example 2016-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid methyl-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-amide

2.3 mg (12 μmol) 2-methylaminomethyl-3H-quinazolin-4-one and 1.6 mg (12μmol) DIPEA were placed in 350 μL DMF. 4.0 mg (10 μmol) of6-[4-(7-methoxy-2-oxo-1,2,4,5-tetra-hydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 1.3 mg (10 μmol) DIPEA in 100 μL DMF were activated with 3.5 mg(11 μmol) TBTU in 50 μL DMF and then added dropwise. The reactionmixture was stirred overnight. 15 μL of an aqueous 2M potassiumcarbonate solution were added and the mixture was stirred for a furtherhour. The precipitate formed was allowed to settle and the supernatantsolution was pipetted off and concentrated to dryness by rotaryevaporation.

Yield: 2.2 mg

ESI-MS: m/z=569 (M+H)⁺

Example 2023-{1-[6-(7,7-dimethyl-3-trifluoromethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

0.11 g (0.28 mmol) TBTU were added to 0.10 g (0.25 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid, 90 mg (0.32 mmol)7,7-dimethyl-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinehydrochloride and 0.12 mL TEA in 1.0 mL DMF and the mixture was stirredfor 4 h at RT. Then the reaction mixture was purified by preparativeHPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 40 mg (25% of theory)

ESI-MS: m/z=599 (M+H)⁺

R_(t) (HPLC-MS): 3.11 min (method E)

Example 2033-(5-fluoroindoline-1-carbonyl)-5-(4-(7-methoxy-2-oxo-4,5-dihydro-1H-benzo[d][1,3]-diazepin-3(2H)-yl)piperidin-1-yl)pyridine-1-oxide

Under an argon atmosphere 5.0 mg (0.02 mmol) palladium(II)acetate and 14mg (20 μmol) BINAP were added to 69 mg (0.25 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,84 mg (0.25 mmol)3-bromo-5-(5-fluoroindoline-1-carbonyl)-pyridine-1-oxide and 0.12 g(0.38 mmol) caesium carbonate in 4.0 mL dioxane and the mixture wasstirred overnight at 120° C. The reaction mixture was then evaporateddown and the residue was dissolved in DMF/MeOH and purified bypreparative HPLC-MS. The product-containing fractions were combined, theorganic solvent was evaporated down and the residue was made alkalinewith a 1N aqueous sodium hydroxide solution. The precipitate formed wassuction filtered, washed with water and dried under HV.

Yield: 40 mg (30% of theory)

ESI-MS: m/z=532 (M+H)⁺

R_(t) (HPLC-MS): 1.44 min (method C)

Example 2041-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-(3-hydroxy-prop-1-ynyl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

Under an argon atmosphere 44 mg (0.34 mmol)3-trimethylsilanyl-prop-2-yn-1-ol, 50 μL TEA, 13 mg1,1′-bis(diphenylphosphine)ferrocene dichloropalladium (II) and 3 mg (20μmol) copper(I) iodide were added to 0.10 g (0.17 mmol)1-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-iodo-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-onein 4.0 mL 1,4-dioxane. Then 0.36 mL (0.36 mmol) of a 1 molartetrabutylammonium fluoride solution in THF were added dropwise and themixture was then stirred for 4 h at 80° C. The reaction mixture wasmixed with water and the precipitate formed was suction filtered. Theprecipitate was stirred in 6 mL DMF and suction filtered. The filtratewas purified by preparative HPLC-MS. The product-containing fractionswere combined and freeze-dried.

Yield: 0.4 mg (0.5% of theory)

ESI-MS: m/z=513 (M+H)⁺

R_(t) (HPLC-MS): 1.44 min (method C)

Example 2056′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo-[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-3′-carbonitrile

150 mg (0.50 mmol)4-chloro-6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-nicotinonitrile, 137mg (0.50 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 103 mg (0.75 mmol) potassium carbonate in 2 mL DMF were stirred for10 h at 130° C. Then the reaction mixture was diluted with 4 mL DMF andthe precipitate formed was suction filtered. The filtrate was purifiedby preparative HPLC-MS. The product-containing fractions were combinedand freeze-dried.

Yield: 10 mg (4% of theory)

ESI-MS: m/z=541 (M+H)⁺

R_(t) (HPLC-MS): 1.68 min (method C)

Example 2063-{1-[6-(3-hydroxymethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

100 mg (0.25 mmol) of6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 50 mg (0.32 mmol) (2,3-dihydro-1H-indol-3-yl)-methanol in 50 μL(0.27 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol)TBTU and the mixture was stirred for 5 h at RT. Then the reactionmixture was purified by preparative HPLC-MS. The product-containingfractions were combined and evaporated down by roughly half. Theprecipitated solid was suction filtered and dried.

Yield: 69 mg (52% of theory)

ESI-MS: m/z=529 (M+H)⁺

R_(t) (HPLC-MS): 2.87 min (method E)

Example 2073-[6′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-2′-methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

125 mg (0.43 mmol)(4-chloro-6-methyl-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone,118 mg (0.43 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 89 mg (0.65 mmol) potassium carbonate in 2.0 mL NMP were stirred for10 h at 130° C. Then the reaction mixture was purified by preparativeHPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 33 mg (14% of theory)

ESI-MS: m/z=530 (M+H)⁺

R_(t) (HPLC-MS): 3.07 min (method B)

Example 2083-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-6-methoxy-1H-quinolin-2-one

25 mg (70 μmol) 6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one, 20 mg (70μmol)(6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanoneand 50 μL (0.29 mmol) DIPEA were stirred in 2 mL DMF overnight at RT.Then the reaction mixture was diluted with DMF and purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 4 mg (11% of theory)

ESI-MS: m/z=500 (M+H)⁺

R_(t) (HPLC-MS): 1.56 min (method C)

Example 2093-{1-[6-(6-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

100 mg (0.25 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 35 mg (0.26 mmol) 6-fluoro-2,3-dihydro-1H-indole in 0.10 mL(0.71 mmol) TEA and 1.5 mL DMF were combined with 90 mg (0.28 mmol) TBTUand stirred for 1 h at RT. Then the reaction mixture was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 58 mg (44% of theory)

ESI-MS: m/z=517 (M+H)⁺

R_(t) (HPLC-MS): 1.56 min (method C)

Example 2103-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-3,4-dihydro-1H-pyrido[4,3-d]pyrimidin-2-one

70 mg (0.25 mmol)(6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone,60 mg (0.26 mmol)3-piperidin-4-yl-3,4-dihydro-1H-pyrido[4,3-d]pyrimidin-2-one and 50 μL(0.30 mmol) DIPEA in 5.0 mL DMF were shaken for 2 h at RT. Then thereaction mixture was poured onto water, stirred and the precipitateformed was suction filtered. This was washed with diisopropylether anddried.

Yield: 26 mg (22% of theory)

ESI-MS: m/z=474 (M+H)⁺

R_(t) (HPLC-MS): 1.20 min (method C)

Example 2113-[5′-ethynyl-2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,4′]-bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

86 μL (86 μmol) of a 1N tetrabutylammonium fluoride solution in THF wereadded to 35 mg (57 mol)3-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-trimethylsilanyl-ethynyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-diazepin-2-onein 1.5 mL THF and the mixture was stirred for 3 h at RT. Then thereaction mixture was combined with a 0.1 molar aqueous hydrochloric acidsolution and the precipitate formed was suction filtered.

Yield: 8 mg (26% of theory)

ESI-MS: m/z=540 (M+H)⁺

R_(t) (HPLC-MS): 1.56 min (method C)

Example 2121-[6′-chloro-4′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

0.74 g (3.4 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 1.0 g (3.2mmol)(2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanoneand 0.65 mL (3.8 mmol) DIPEA in 10 mL DMF were stirred for 2 h at RT.Then the reaction mixture was evaporated down, the residue was mixedwith water and stirred for 30 min at RT. The precipitated solid wassuction filtered, stirred with diisopropylether and isopropanol andsuction filtered again. After drying the crude product was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 350 mg (22% of theory)

ESI-MS: m/z=493 (M+H)⁺

R_(t) (HPLC-MS): 1.73 min (method O)

Example 2133-{1-[6-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

70 mg (0.25 mmol)(6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone,60 mg (0.26 mmol)3-piperidin-4-yl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one and 52 μL(0.30 mmol) DIPEA in 5.0 mL DMF were shaken for 2 h at RT. Then thereaction mixture was poured onto water, stirred and the precipitateformed was suction filtered. This was washed with diisopropylether anddried.

Yield: 99 mg (83% of theory)

ESI-MS: m/z=474 (M+H)⁺

R_(t) (HPLC-MS): 1.43 min (method C)

Example 2141-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carbonyl]-1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one

67 mg (0.17 mmol)4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylicacid and 30 mg (0.17 mmol)1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one in 56 μL (0.40mmol) TEA and 1.8 mL DMF were combined with 58 mg (0.18 mmol) TBTU andstirred overnight at RT. Then the reaction mixture was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 70 mg (75% of theory)

ESI-MS: m/z=553 (M+H)⁺

R_(t) (HPLC-MS): 2.84 min (method E)

Example 2151-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carbonyl]-1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one

67 mg (0.17 mmol)4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid and 30 mg (0.17 mmol)1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one in 56 μL (0.40mmol) TEA and 1.8 mL DMF were combined with 58 mg (0.18 mmol) TBTU andstirred overnight at RT. Then the reaction mixture was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 44 mg (47% of theory)

ESI-MS: m/z=553 (M+H)⁺

R_(t) (HPLC-MS): 3.00 min (method E)

Example 2163-[6′-chloro-4′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

1.0 g (3.2 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,0.94 g (3.4 mmol)(2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanoneand 0.65 mL (3.8 mmol) DIPEA in 10 mL DMF were stirred for 2 h at RT.Then the reaction mixture was evaporated down, the residue was mixedwith water and stirred for 30 min at RT. The precipitated solid wassuction filtered, stirred with diisopropylether and isopropanol andsuction filtered again. After drying the crude product was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 750 mg (42% of theory)

ESI-MS: m/z=550 (M+H)⁺

R_(t) (HPLC-MS): 1.96 min (method O)

Example 2173-{-[6-(5-hydroxymethyl-4.7-dihydro-5H-thieno[2,3-c]pyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

100 mg (0.25 mmol)4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid and 50 mg (0.28 mmol)(4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-5-yl)-methanol in 50 μL (0.36mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU andthe mixture was stirred for 5 h at RT. Then the reaction mixture waspurified by preparative HPLC-MS. The product-containing fractions werecombined and evaporated down roughly by half. The precipitate formed wassuction filtered and dried.

Yield: 40 mg (29% of theory)

ESI-MS: m/z=549 (M+H)⁺

R_(t) (HPLC-MS): 2.89 min (method E)

Example 2184-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-2-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-benzonitrile

70 mg (0.19 mmol)4-cyano-3-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-benzoicacid and 30 mg (0.21 mmol) 5-fluoro-2,3-dihydro-(1H)-indole in 0.10 mL(0.72 mmol) TEA and 1.5 mL DMF were mixed with 65 mg (0.20 mmol) TBTUand the mixture was stirred for 1 h at RT. Then the reaction mixture waspurified by preparative HPLC-MS. The product-containing fractions werecombined and freeze-dried.

Yield: 4 mg (4% of theory)

ESI-MS: m/z=483 (M+H)⁺

R_(t) (HPLC-MS): 1.64 min (method C)

Example 2191-{1-[6-(3-hydroxymethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

85 mg (0.25 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 50 mg (0.32 mmol) (2,3-dihydro-1H-indol-3-yl)-methanol in 50 μL(0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol)TBTU and stirred for 5 h at RT. Then the reaction mixture was purifiedby preparative HPLC-MS. The product-containing fractions were combinedand freeze-dried.

Yield: 57 mg (46% of theory)

ESI-MS: m/z=472 (M+H)⁺

R_(t) (HPLC-MS): 1.11 min (method C)

Example 2206-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid(1H-indazol-4-yl)-amide

100 mg (0.25 mmol)4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid and 34 mg (0.25 mmol) 4-amino-indazole in 74 mμL (0.53 mmol) TEAand 1.5 mL DMF were combined with 89 mg (0.28 mmol) TBTU and the mixturewas stirred overnight at RT. Then the reaction mixture was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 24 mg (19% of theory)

ESI-MS: m/z=513 (M+H)⁺

R_(t) (HPLC-MS): 1.35 min (method C)

Example 2213-{1-[3-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-phenyl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

Under an argon atmosphere 7 mg (31 μmol) palladium(II) acetate and 20 mg(32 μmol) BINAP were added to 86 mg (0.31 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,0.10 g (0.31 mmol)(3-bromo-phenyl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.16 g(0.48 mmol) caesium carbonate in 4.0 mL dioxane, and the mixture wasstirred overnight at 120° C. The reaction mixture was then evaporateddown and the residue was dissolved in DMF/MeOH and purified bypreparative HPLC-MS.

The product-containing fractions were combined and freeze-dried.

Yield: 10 mg (5% of theory)

ESI-MS: m/z=515 (M+H)⁺

R_(t) (HPLC-MS): 1.69 min (method C)

Example 2227-methoxy-3-{1-[6-(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

83 mg (0.21 mmol)4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylicacid and 37 mg (0.24 mmol) 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepinein 0.13 mL (0.72 mmol) DIPEA and 1.0 mL DMF were combined with 77 mg(0.24 mmol) TBTU and the mixture was stirred overnight at RT. Then thereaction mixture was purified by preparative HPLC-MS. Theproduct-containing fractions were combined and freeze-dried.

Yield: 14 mg (12% of theory)

ESI-MS: m/z=534 (M+H)⁺

R_(t) (HPLC-MS): 1.30 min (method C)

Example 2231-{6-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carbonyl}-1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one

63 mg (0.17 mmol)6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 30 mg (0.17 mmol)1,2,2a,5-tetrahydro-3H-pyrrolo-[4,3,2-de]quinolin-4-one in 56 μL (0.40mmol) TEA and 1.8 mL DMF were mixed with 58 mg (0.18 mmol) TBTU and themixture was stirred overnight at RT. Then the reaction mixture waspurified by preparative HPLC-MS. The product-containing fractions werecombined and freeze-dried.

Yield: 60 mg (67% of theory)

ESI-MS: m/z=524 (M+H)⁺

R_(t) (HPLC-MS): 3.20 min (method E)

Example 2247-methoxy-3-(1-(6-(1′-methyl-2′,3′-dihydro-1′H-spiro[cyclopentan-1,4′-isoquinolin]-2′-yl-carbonyl)-pyrimidin-4-yl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one

42 mg (0.11 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]pyrimidine-4-carboxylicacid and 25 mg (0.11 mmol)1′-methyl-2′,3′-dihydro-1′H-spiro[cyclopentan-1,4′-isoquinolinehydrochloride in 63 μL (0.36 mmol) DIPEA and 1.0 mL DMF were combinedwith 39 mg (0.12 mmol) TBTU and the mixture was stirred overnight at RT.Then the reaction mixture was purified by preparative HPLC-MS. Theproduct-containing fractions were combined and partially evaporateddown. The precipitate formed was suction filtered and dried. Thefiltrate was freeze-dried. The residue remaining was identical to theprecipitate.

Yield: 33 mg (54% of theory)

ESI-MS: m/z=581 (M+H)⁺

R_(t) (HPLC-MS): 1.74 min (method C)

Example 2253-{1-[6-(2-hydroxymethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

100 mg (0.25 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 45 mg (0.30 mmol) (2,3-dihydro-1H-indole-2-yl)-methanol in 50μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol)TBTU and stirred overnight at RT. Then the reaction mixture was purifiedby preparative HPLC-MS. The product-containing fractions were combinedand partially evaporated down. The precipitate formed was suctionfiltered and dried.

Yield: 45 mg (30% of theory)

ESI-MS: m/z=529 (M+H)⁺

R_(t) (HPLC-MS): 2.97 min (method E)

Example 2263-{1-[6-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

83 mg (0.21 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 37 mg (0.24 mmol) 1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine in0.10 mL (0.72 mmol) TEA and 2.0 mL DMF were mixed with 77 mg (0.24 mmol)TBTU and the mixture was stirred overnight at RT. Then the reactionmixture was purified by preparative HPLC-MS. The product-containingfractions were combined, the acetonitrile was evaporated down and theresidue was dried.

Yield: 43 mg (41% of theory)

ESI-MS: m/z=502 (M+H)⁺

R_(t) (HPLC-MS): 1.32 min (method C)

Example 2271-{1-[6-(5-hydroxymethyl-4.7-dihydro-5H-thieno[2,3-c]pyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

85 mg (0.25 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 50 mg (0.32 mmol)(4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-5-yl)-methanol in 50 μL (0.36mmol) TEA and 0.90 mL DMF were combined with 80 mg (0.25 mmol) TBTU andthe mixture was stirred for 5 h at RT. Then the reaction mixture waspurified by preparative HPLC-MS. The product-containing fractions werecombined and freeze-dried.

Yield: 25 mg (20% of theory)

ESI-MS: m/z=492 (M+H)⁺

R_(t) (HPLC-MS): 1.12 min (method C)

Example 2286-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid(1H-indazol-4-yl)-amide

100 mg (0.29 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 39 mg (0.29 mmol) 1H-indazole-4-ylamine in 87 mL (0.62 mmol)TEA and 1.5 mL DMF were combined with 104 mg (0.32 mmol) TBTU andstirred overnight at RT. Then the reaction mixture was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 6 mg (5% of theory)

ESI-MS: m/z=456 (M+H)⁺

R_(t) (HPLC-MS): 1.10 min (method C)

Example 2291-{1-[6-(2-hydroxymethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

85 mg (0.25 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 45 mg (0.30 mmol) (2,3-dihydro-1H-indole-2-yl)-methanol in 50μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol)TBTU and stirred overnight at RT. Then the reaction mixture was purifiedby preparative HPLC-MS. The product-containing fractions were combinedand freeze-dried.

Yield: 36 mg (29% of theory)

ESI-MS: m/z=472 (M+H)⁺

R_(t) (HPLC-MS): 2.44 min (method E)

Example 2303-(1-{6-[2-(3,5-difluoro-phenyl)-5,5-dimethyl-piperidine-1-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

65 mg (0.16 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 70 mg (0.16 mmol)(S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine in 0.04 mL (0.72 mmol)DIPEA and 0.80 mL DMF were combined with 65 mg (0.17 mmol) HATU andstirred overnight at RT. Then the reaction mixture was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 40 mg (43% of theory)

ESI-MS: m/z=605 (M+H)⁺

Example 2313-(1-(6-(1,4,5,6,7,8-hexahydropyrazolo[4,3-d]azepine-6-carbonyl)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one

65 mg (0.16 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 35 mg (0.20 mmol) 1,4,5,6,7,8-hexahydro-pyrazolo[4,3-d]azepinehydrochloride in 80 μL (0.57 mmol) TEA and 0.80 mL DMF were combinedwith 68 mg (0.18 mmol) HATU and the mixture was stirred overnight at RT.Then the reaction mixture was purified twice by preparative HPLC-MS. Theproduct-containing fractions were combined and freeze-dried.

Yield: 21 mg (25% of theory)

ESI-MS: m/z=517 (M+H)⁺

R_(t) (HPLC-MS): 3.29 min (method B)

Example 2327-methoxy-3-{1-[6-(6-methoxy-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

80 mg (0.20 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]pyrimidine-4-carboxylicacid and 30 mg (0.20 mmol) 6-methoxy-2,3-dihydro-1H-indole in 50 μL(0.36 mmol) TEA and 1.5 mL DMF were combined with 70 mg (0.22 mmol) TBTUand the mixture was stirred for 1 h at RT. Then the reaction mixture waspurified by preparative HPLC-MS. The product-containing fractions werecombined and freeze-dried.

Yield: 35 mg (33% of theory)

ESI-MS: m/z=529 (M+H)⁺

R_(t) (HPLC-MS): 1.55 min (method C)

Example 2336-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid(1H-indazol-5-yl)-amide

100 mg (0.29 mmol)6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 39 mg (0.29 mmol) 5-aminobenzopyrrazole in 87 μL (0.62 mmol)TEA and 1.5 mL DMF were combined with 104 mg (0.32 mmol) TBTU and themixture was stirred overnight at RT. Then the reaction mixture waspurified by preparative HPLC-MS. The product-containing fractions werecombined and freeze-dried.

Yield: 45 mg (34% of theory)

ESI-MS: m/z=456 (M+H)⁺

R_(t) (HPLC-MS): 1.18 min (method ?)

Example 2343-{1-[6-(2-ethyl-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

110 mg (0.40 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,103 mg (0.36 mmol)(6-chloro-pyrimidin-4-yl)-(2-ethyl-2,3-dihydro-indol-1-yl)-methanone and0.14 mL (0.80 mmol) DIPEA in 3.0 mL DMF were stirred overnight at RT.Then the reaction mixture was purified by preparative HPLC-MS. Theproduct-containing fractions were combined, the organic solvent wasevaporated down and the residue was neutralised with 1N aqueous sodiumhydroxide solution. The precipitate formed was suction filtered, washedwith water and dried under HV.

Yield: 110 mg (52% of theory)

ESI-MS: m/z=527 (M+H)⁺

R_(t) (HPLC-MS): 1.62 min (method C)

Example 2356-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid(7-methyl-1H-indazol-5-yl)-amide

100 mg (0.25 mmol)6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylicacid and 37 mg (0.25 mmol) 7-methyl-1H-indazol-5-amine in 74 μL (0.53mmol) TEA and 1.5 mL DMF were combined with 89 mg (0.28 mmol) TBTU andstirred overnight at RT. Then the reaction mixture was purified bypreparative HPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 7 mg (5% of theory)

ESI-MS: m/z=527 (M+H)⁺

R_(t) (HPLC-MS): 2.07 min (method S)

Example 2367-methoxy-3-{1-[6-(5-oxo-octahydro-pyrrolo[3,2-b]pyridine-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one

0.17 g (0.28 mmol)3-{(1-[6-(5-benzyloxy-pyrrolo[3,2-b]pyridine-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-oneand 50 mg palladium (Pd/C 5%) in 20 ml EtOH were hydrogenated forseveral hours at RT in a hydrogen atmosphere. As no reaction took placean additional 10 ml THF were added and hydrogenation was continued at50° C. Then the catalyst was eliminated by suction filtering and thefiltrate was evaporated down. The residue was purified by preparativeHPLC-MS. The product-containing fractions were combined andfreeze-dried.

Yield: 16 mg (11% of theory)

ESI-MS: m/z=520 (M+H)⁺

R_(t) (HPLC-MS): 2.17 min (method E)

The following Examples describe the preparation of pharmaceuticalformulations that contain as active substance any desired compound ofgeneral formula I:

Example I Capsules for Powder Inhalation Containing 1 Mg of ActiveIngredient Composition:

1 capsule for powder inhalation contains:

active ingredient  1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg71.0 mg

Method of Preparation:

The active ingredient is ground to the particle size required forinhaled substances. The ground active ingredient is homogeneously mixedwith the lactose. The mixture is transferred into hard gelatinecapsules.

Example II Inhalable Solution for Respimat® Containing 1 mg of ActiveIngredient Composition:

1 puff contains:

active ingredient 1.0 mg benzalkonium chloride 0.002 mg disodium edetate0.0075 mg purified water ad 15.0 μl

Method of Preparation:

The active ingredient and benzalkonium chloride are dissolved in waterand transferred into Respimat® cartridges.

Example III Inhalable Solution for Nebulisers Containing 1 mg of ActiveIngredient Composition:

1 vial contains:

active ingredient 0.1 g sodium chloride 0.18 g benzalkonium chloride0.002 g purified water ad 20.0 ml

Method of Preparation:

The active ingredient, sodium chloride and benzalkonium chloride aredissolved in water.

Example IV Propellant Gas-Operated Metered Dose Aerosol Containing 1 mgof Active Ingredient Composition:

1 puff contains:

active ingredient 1.0 mg lecithin 0.1% propellant gas ad 50.0 μl

Method of Preparation:

The micronised active ingredient is homogeneously suspended in themixture of lecithin and propellant gas. The suspension is transferredinto a pressurised container with a metering valve.

Example V Nasal Spray Containing 1 mg of Active Ingredient Composition:

active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride0.025 mg disodium edetate 0.05 mg purified water ad 0.1 ml

Method of Preparation:

The active ingredient and the excipients are dissolved in water andtransferred into a suitable container.

Example VI Injectable Solution Containing 5 mg of Active Substance Per 5ml Composition:

active substance 5 mg glucose 250 mg human serum albumin 10 mgglycofurol 250 mg water for injections ad 5 ml

Preparation:

Glycofurol and glucose are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred into ampoulesunder nitrogen gas.

Example VII Injectable Solution Containing 100 mg of Active SubstancePer 20 ml Composition:

active substance 100 mg monopotassium dihydrogen phosphate = KH₂PO₄ 12mg disodium hydrogen phosphate = Na₂HPO₄*2H₂O 2 mg sodium chloride 180mg human serum albumin 50 mg Polysorbate 80 20 mg water for injectionsad 20 ml

Preparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate anddisodium hydrogen phosphate are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred intoampoules.

Example VIII Lyophilisate Containing 10 mg of Active SubstanceComposition:

Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg waterfor injections ad 2 ml

Preparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into vials; freeze-dried.

Solvent for Lyophilisate:

Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad10 ml

Preparation:

Polysorbate 80 and mannitol are dissolved in water for injections (WfI);transferred into ampoules.

Example IX Tablets Containing 20 mg of Active Substance Composition:

active substance 20 mg lactose 120 mg  corn starch 40 mg magnesiumstearate  2 mg Povidone K 25 18 mg

Preparation:

Active substance, lactose and corn starch are homogeneously mixed;granulated with an aqueous solution of Povidone; mixed with magnesiumstearate; compressed in a tablet press; weight of tablet 200 mg.

Example X Capsules Containing 20 mg Active Substance Composition:

active substance 20 mg corn starch 80 mg highly dispersed silica 5 mgmagnesium stearate 2.5 mg

Preparation:

Active substance, corn starch and silica are homogeneously mixed; mixedwith magnesium stearate; the mixture is packed into size for 3 hardgelatine capsules in a capsule filling machine.

Example XI Suppositories Containing 50 mg of Active SubstanceComposition:

active substance  50 mg hard fat (Adeps solidus) q.s. Ad 1700 mg

Preparation:

Hard fat is melted at about 38° C.; ground active substance ishomogeneously dispersed in the molten hard fat; after cooling to about35° C. it is poured into chilled moulds.

Example XII Injectable Solution Containing 10 mg of Active Substance Per1 ml Composition:

active substance 10 mg mannitol 50 mg human serum albumin 10 mg waterfor injections ad 1 ml

Preparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into ampoules under nitrogen gas.

1. A compound of the formula I

wherein R¹ denotes a group of general formula II

wherein G-L denotes N,N—C(R^(5.1))₂, C═C(R^(5.1)), C═N, C(R^(5.1)),C(R^(5.1))—C(R^(5.1))₂, C(R^(5.1))—C(R^(5.1))₂—C(R^(5.1))₂,C═C(R^(5.1))—C(R^(5.1))₂, C(R^(5.1))—C(R^(5.1))═C(R^(5.1)),C(R^(5.1))—C(R^(5.1))₂—N(R^(5.2)), C═C(R^(5.1))—N(R^(5.2)),C(R^(5.1))—C(R^(5.1))═N, C(R^(5.1))—N(R^(5.2))—C(R^(5.1))₂,C═N—C(R^(5.1))₂, C(R^(5.1))—N═C(R^(5.1)),C(R^(5.1))—N(R^(5.2))—N(R^(5.2)), C═N—N(R^(5.2)),N—C(R^(5.1))₂—C(R^(5.1))₂, N—C(R^(5.1))═C(R^(5.1)),N—C(R^(5.1))₂—N(R^(5.2)), N—C(R^(5.1))═N,N—N(R^(5.2))—C(R^(5.1))₂ orN—N═C(R^(5.1)), Q-T denotes C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶),C(R⁶)₂—C(═O), C(═O)—C(R⁶)₂, C(R⁶)₂—S(O), or C(R⁶)₂—N(R⁶), while a groupC(R⁶)₂ contained in Q-T may also denote a cyclic group that is selectedfrom among C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl or heterocyclyl, or in agroup C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶) contained in Q-T ineach case a group R⁶ together with an adjacent group R⁶ and the atoms towhich these groups are attached may also denote a C₃₋₆-cycloalkyl,C₅₋₆-cycloalkenyl, heterocyclyl-, aryl- or heteroaryl group which may besubstituted independently of one another by 1, 2 or 3 substituentsR^(6.1), R² denotes (a) H, (b) F, —CN, C₁₋₃-alkyl, —CO₂—R^(2.1) or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(2.1) denotes H or C₁₋₆-alkyl, R³ denotes (a) H, (b)C₁₋₆-alkylene-R^(3.1), (c) a C₃₋₆-cycloalkyl group substituted by one ortwo groups R^(3.2), (d) a C₅₋₇-cycloalkenyl group substituted by one ortwo groups R^(3.2), (e) an aryl group substituted by one or two groupsR^(3.2), (f) a heterocyclyl group substituted by one or two groupsR^(3.2), (g) a C₅₋₇-cycloalkyl group which may be fused to an aryl orheteroaryl group and is additionally substituted by one or two groupsR^(3.2), (h) a heteroaryl group substituted by one or two groupsR^(3.2), (i) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.1) denotes (a) H, (b) anaryl group substituted by the groups R^(3.1.1) and R^(3.1.2), (c) aheteroaryl group substituted by the groups R^(3.1.1) and R^(3.1.2),R^(3.1.1) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —CN,—O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl, —NR^(3.1.1.1)R^(3.1.1.2),—S(O)_(m)—C₁₋₃-alkyl, —NR^(3.1.1.1-)C(O)—C₁₋₃-alkyl,—C(O)—NR^(3.1.1.1)R^(3.1.1.2), —C(O)—O—R^(3.1.1.3),—NR^(3.1.1,1-)C(O)—O—C₁₋₃-alkyl, —O—C(O)—NR^(3.1.1.1)R^(3.1.1.2), (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.1.1.1) denotes H,C₁₋₃-alkyl and R^(3.1.1.2) denotes H, C₁₋₃-alkyl, or R^(3.1.1.1) andR^(3.1.1.2) together with the nitrogen atom to which they are bound alsodenote a group selected from among morpholinyl, thiomorpholinyl,piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl,while the group may additionally be substituted by one or twosubstituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl andCF₃, R^(3.1.1.3) denotes H, C₁₋₃-alkyl, R^(3.1.2) denotes (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or R^(3.2) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl,—NR^(3.2.1)R^(3.2.2), —S(O)_(m)—C₁₋₃-alkyl, —NR^(3.2.1)—C(O)—C₁₋₃-alkyl,—C(O)—NR^(3.2.1)R^(3.2.2), —C(O)—O—R^(3.2.3),—NR^(3.2.1)—C(O)—O—C₁₋₃-alkyl, —O—C(O)—NR^(3.2.1)R^(3.2.2), (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.2.1) denotes H,C₁₋₃-alkyl and R^(3.2.2) denotes H, C₁₋₃-alkyl, or R^(3.2.1) andR^(3.2.2) together with the nitrogen atom to which they are bound alsodenote a group selected from among morpholinyl, thiomorpholinyl,piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl,while the group may additionally be substituted by one or twosubstituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl andCF₃, R^(3.2.3) denotes H, C₁₋₃-alkyl, R⁴ denotes (a) H, (b)C₁₋₆-alkylene-R^(4.1), (c) a C₃₋₆-cycloalkyl group substituted by one ortwo groups R^(4.2), (d) a C₅₋₇-cycloalkenyl group substituted by one ortwo groups R^(4.2), (e) an aryl group substituted by one or two groupsR^(4.2), (f) a heterocyclyl group substituted by one or two groupsR^(4.2), (g) a C₅₋₇-cycloalkyl group which may be fused to an aryl orheteroaryl group and is additionally substituted by one or two groupsR^(4.2), (h) a heteroaryl group substituted by one or two groupsR^(4.2), (i) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.1) denotes (a) H, (b) anaryl group substituted by the groups R^(4.1.1) and R^(4.1.2), (c) aheteroaryl group substituted by the groups R^(4.1.1) and R^(4.1.2),R^(4.1.1) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —CN,—O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl, —NR^(4.1.1.1)R^(4.1.1.2),—S(O)_(m)—C₁₋₃-alkyl, —NR^(4.1.1,1-)C(O)—C₁₋₃-alkyl,—C(O)—NR^(4.1.1.1)R^(4.1.1.2)C(O)—O—R^(4.1.1.3),—NR^(4.1.1,1-)C(O)—O—C₁₋₃-alkyl, —O—C(O)—NR^(4.1.1.1)R^(4.1.1.2), (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.1.1.1) denotes H,C₁₋₃-alkyl and R^(4.1.1.2) denotes H, C₁₋₃-alkyl, or R^(4.1.1.1) andR^(4.1.1.2) together with the nitrogen atom to which they are bound alsodenote a group selected from among morpholinyl, thiomorpholinyl,piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl,while the group may additionally be substituted by one or twosubstituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl andCF₃, R^(4.1.1.3) denotes H, C₁₋₃-alkyl, R^(4.1.2) denotes (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or R^(4.2) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl,—NR^(4.2.1)R^(4.2.2), —S(O)_(m)—C₁₋₃-alkyl, —NR^(4.2.1)C(O)C₁₋₃-alkyl,—C(O)—NR^(4.2.1)R^(4.2.2), —C(O)—O—R^(4.2.3),—NR^(4.2.1)—C(O)—O—C₁₋₃-alkyl, —O—C(O)—NR^(4.2.1)R^(4.2.2), (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.2.1) denotes H,C₁₋₃-alkyl and R^(4.2.2) denotes H, C₁₋₃-alkyl, or R^(4.2.1) andR^(4.2.2) together with the nitrogen atom to which they are bound alsodenote a group selected from among morpholinyl, thiomorpholinyl,piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl,while the group may additionally be substituted by one or twosubstituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl andCF₃, R^(4.2.3) denotes H, C₁₋₃-alkyl, R³ and R⁴ together with thenitrogen atom to which they are bound denote: (a) a saturated 5, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4), (b) a saturated 5,6- or 7-membered heterocyclic group which is substituted at two adjacentcarbon atoms by a group R^(4.3) and R^(4.4) in each case, (c) asaturated 5,6- or 7-membered heterocyclic group which is substituted ata carbon atom by a group R^(4.3) or by two groups R^(4.3) and R^(4.4)and is additionally fused to a 5-, 6- or 7-membered cycloalkyl orheterocyclyl group, while the fused-on cycloalkyl or heterocyclyl groupis substituted by 1, 2 or 3 groups R^(4.5), (d) a monounsaturated 5-, 6-or 7-membered heterocyclic group which is substituted at a carbon atomby a group R^(4.3) or by two groups R^(4.3) and R^(4.4) and isadditionally fused to a phenyl group, while the fused-on phenyl group issubstituted by 1, 2 or 3 groups R^(4.5), (e) a monounsaturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4) and is additionallyfused to a 5- or 6-membered heteroaryl group, while the fused-onheteroaryl group is substituted by 1, 2 or 3 groups R^(4.5), or (f) aheteroaryl group which is substituted at 1, 2 or 3 carbon atoms by agroup R^(4.5) in each case, R^(4.3) independently of one another denote(a) H, C₁₋₃-alkyl, C₂₋₄-alkenyl, C₂₋₆-alkynyl, aryl,—C₁₋₃-alkylene-R^(4.3.1), C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F,—O—C₁₋₃-alkyl, —OH, —CN, (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, (c)a 5- or 6-membered heteroaryl group, (d) aryl, R^(4.3.1) denotes H, HO,C₁₋₃-alkyl-O—, C₁₋₃-alkyl-O—C(O)—, CN, —NH₂, (C₁₋₄-alkyl)-NH—,(C₁₋₄-alkyl)₂N—, C₃₋₆-cycloalkyl-, heterocyclyl, heteroaryl, aryl,R^(4.4) denotes (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or (b) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.3) and R^(4.4) togetherwith the carbon atom to which they are attached may also denote aC₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl or heterocyclyl group, R^(4.5)independently of one another denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl, —S(O)C₁₋₃-alkyl, —NR^(4.5.2)R^(4.5.3), —CN,—C(O)—O—R^(4.5.1), —C(O)—NR^(4.5.2)R^(4.5.3), (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, (d) aryl, heteroaryl, R^(4.5.1) denotes H, C₁₋₃-alkyl,R^(4.5.2) denotes H, C₁₋₃-alkyl, R^(4.5.3) denotes H, C₁₋₃-alkyl, orR^(4.5.2) and R^(4.5.3) together with the nitrogen atom to which theyare bound also denote a group selected from among morpholinyl,thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl andazetidinyl, while the group may additionally be substituted by one ortwo substituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyland CF₃, R^(5.1) denotes (a) H, (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,(c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(5.2) denotes H orC₁₋₆-alkyl, R⁶ independently of one another denote (a) H, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, (b) an aryl groupoptionally substituted by 1, 2 or 3 substituents R^(6.2), wherein thesubstituents R^(6.2) may be identical or different, (c) a heteroarylgroup optionally substituted by 1, 2 or 3 substituents R^(6.2), whereinthe substituents R^(6.2) may be identical or different, (d) aheterocyclic group optionally substituted by 1, 2 or 3 substituentsR^(6.2), wherein the substituents R^(6.2) may be identical or different,R^(6.1) denotes (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b)—O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂—R⁷, —C(O)—NR⁸R⁹,—O—C(O)—NR⁸R⁹, —NR⁷—C(O)—NR⁸R⁹, —NR⁸—C(O)—R⁹, —NR⁸—C(O)—O—R⁹,—SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹, —NR'-C(O)—NR⁸R⁹,—O—C(O)—R⁷, (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, (d) an arylgroup substituted by 1, 2 or 3 substituents R⁷, wherein the substituentsR⁷ may be identical or different, (e) a heteroaryl group substituted by1, 2 or 3 substituents R⁷, wherein the substituents R⁷ may be identicalor different, (f) a heterocyclic group substituted by 1, 2 or 3substituents R⁷, wherein the substituents R⁷ may be identical ordifferent, R^(6.2) denotes (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b)—O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹, —O—(CO)—NR⁸R⁹,—N(R⁷)—C(O)—NR⁸R⁹, —N(R⁸)—C(O)—R⁹, —N(R⁸)—C(O)—O—R⁹, —SO₂—NR⁸R⁹,—N(R⁸)—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹, —N(R⁷)—C(O)—NR⁸R⁹, —O—C(O)—R⁷or (c) a C₁₋₃-alkyl group wherein each methylene group is substituted byup to two fluorine atoms and each methyl group is substituted by up tothree fluorine atoms, R⁷ denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl,aryl, heteroaryl, benzyl which may be substituted by a group R^(7.1), or(c) a C₁₋₃-alkyl group wherein each methylene group is substituted by upto two fluorine atoms and each methyl group is substituted by up tothree fluorine atoms, R^(7.1) denotes halogen, HO— or C₁₋₆-alkyl-O—, R⁸denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl orbenzyl, wherein the groups may be unsubstituted or substituted byhalogen, HO— or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R⁹ denotes(a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,wherein the groups may be unsubstituted or substituted by halogen, HO—or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene groupis substituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R⁸ and R⁹ together mayalso form a ring which is selected from among azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl, wherein the ring may beunsubstituted or substituted by 1, 2 or 3 substituents R⁷ or fluorine,wherein the substituents R⁷ are independent of one another, m denotesone of the numbers 0, 1 or 2, s denotes one of the numbers 1, 2 or 3, Udenotes N,N-oxide or C—R¹⁹, V denotes N,N-oxide or C—R¹¹, X denotesN,N-oxide or C—R¹², Y denotes N or C—R¹³, while not more than three ofthe previously mentioned groups U, V, X and Y simultaneously represent anitrogen atom, R¹⁰ denotes H, halogen, —CN, C₁₋₃-alkyl, —CF₃,C₂₋₆-alkynyl, HO—C₂₋₆-alkynylene, R¹¹ denotes H, C₁, C₁₋₃-alkyl,—NR^(11.1)R^(11.2) or —O—C₁₋₃-alkyl, R^(11.1) denotes H or C₁₋₆-alkyl,R^(11.2) denotes H or —SO₂—C₁₋₃-alkyl, R¹² denotes H, halogen, —CN,C₁₋₃-alkyl, —CF₃, C₂₋₆-alkynyl and R¹³ denotes H, halogen or C₁₋₃-alkyl,or a tautomer or salt thereof.
 2. A compound of the formula I accordingto claim 1, wherein R¹ denotes a group of general formula II

wherein G-L denotes N,N—C(R^(5.1))₂, C═C(R^(5.1)), C═N, C(R^(5.1)),C(R^(5.1))—C(R^(5.1))₂, C(R^(5.1))—C(R^(5.1))₂—C(R^(5.1))₂,C═C(R^(5.1))—C(R^(5.1))₂, C(R^(5.1))—C(R^(5.1))═C(R^(5.1)),C(R^(5.1))—C(R^(5.1))₂—N(R^(5.2)), C═C(R^(5.1))—N(R^(5.2)),C(R^(5.1))—C(R^(5.1))═N, C(R^(5.1))—N(R^(5.2))—C(R^(5.1))₂,C═N—C(R^(5.1))₂, C(R^(5.1))—N═C(R^(5.1)),C(R^(5.1))—N(R^(5.2))—N(R^(5.2)), C═N—N(R^(5.2)),N—C(R^(5.1))₂—C(R^(5.1))₂, N—C(R^(5.1))═C(R^(5.1)),N—C(R^(5.1))₂—N(R^(5.2)), N—C(R^(5.1))═N,N—N(R^(5.2))—C(R^(5.1))₂ orN—N═C(R^(5.1)), Q-T denotes C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶),C(R⁶)₂—C(═O), C(═O)—C(R⁶)₂, C(R⁶)₂—S(O)_(m) or C(R⁶)₂—N(R⁶), while aC(R⁶)₂ contained in Q-T group may also denote a cyclic group that isselected from among cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,cyclohexenyl, dioxanyl, morpholinyl, thiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S-dioxide, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl andpiperazinyl, or in a group C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶)contained in Q-T in each case a group R⁶ together with an adjacent groupR⁶ and the atoms to which these groups are attached may also denote agroup selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl,thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl, thiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-5-dioxide, 1H-quinolinyl-2-on,azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl,dihydropyranyl and piperazinyl, which may be substituted independentlyof one another by 1, 2 or 3 substituents R^(6.1), R^(5.1) denotes (a) H,(b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- orC₁₋₃-alkyl-O— group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(5.2) denotes H or C₁₋₆-alkyl, R⁶ independently of oneanother denote (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₆-cycloalkyl, (b) an aryl group optionally substituted by 1, 2 or 3substituents R^(6.2), wherein the substituents R^(6.2) may be identicalor different, (c) a heteroaryl group optionally substituted by 1, 2 or 3substituents R^(6.2), wherein the substituents R^(6.2) may be identicalor different, (d) a heterocyclic group optionally substituted by 1, 2 or3 substituents R^(6.2), wherein the substituents R^(6.2) may beidentical or different, R^(6.1) denotes (a) H, halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —O—(CH₂)_(s)—O—R⁷,—CO₂—R⁷, C(O)—NR⁸R⁹, —O—C(O)—NR⁸R⁹, —NR'-C(O)—NR⁸R⁹, —NR⁸—C(O)—R⁹,—NR⁸—C(O)—O—R⁹, —SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹,—NR⁷—C(O)—NR⁸R⁹, —O—C(O)—R⁷, (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, (d)an aryl group with 1, 2 or 3 substituents R⁷, wherein the substituentsR⁷ may be identical or different, (e) a heteroaryl group substituted by1, 2 or 3 substituents R⁷, wherein the substituents R⁷ may be identicalor different, (f) a heterocyclic group substituted by 1, 2 or 3substituents R⁷, wherein the substituents R⁷ may be identical ordifferent, R^(6.2) denotes (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b)—O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹, —O—(CO)—NR⁸R⁹,—N(R⁷)—C(O)—NR⁸R⁹, —N(R⁸)—C(O)—R⁹, —N(R⁸)—C(O)—O—R⁹, —SO₂—NR⁸R⁹,—N(R⁸)—SO₂—R⁹, —S(O)_(m)—R⁸, CN, NR⁸R⁹, —N(R⁷)—C(O)—NR⁸R⁹, —O—C(O)—R⁷ or(c) a C₁₋₃-alkyl group wherein each methylene group is substituted by upto two fluorine atoms and each methyl group is substituted by up tothree fluorine atoms, R⁷ denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl,aryl, heteroaryl, benzyl which may be substituted by a group R^(7.1), or(c) a C₁₋₃-alkyl group wherein each methylene group is substituted by upto two fluorine atoms and each methyl group is substituted by up tothree fluorine atoms, R^(7.1) denotes halogen, HO— or C₁₋₆-alkyl-O—, R⁸denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl orbenzyl, wherein the groups may be unsubstituted or substituted byhalogen, HO— or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R⁹ denotes(a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,wherein the groups may be unsubstituted or substituted by halogen, HO—or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene groupis substituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R⁸ and R⁹ together mayalso form a ring which is selected from among azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl, wherein the ring may beunsubstituted or substituted by 1, 2 or 3 substituents R⁷ or fluorine,wherein the substituents R⁷ are independent of one another, m denotesone of the numbers 0, 1 or 2 and s denotes one of the numbers 1, 2 or 3,or a tautomer or salt thereof.
 3. A compound of the formula I accordingto claim 1, wherein R¹ denotes a group of general formulae

wherein Q-T denote C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶), C(R⁶)₂—C(═O),C(═O)—C(R⁶)₂, C(R⁶)₂—S(O)_(m) or C(R⁶)₂—N(R⁶), while in a groupC(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶) contained in Q-T in each casea group R⁶ together with an adjacent group R⁶ and the atoms to whichthese groups are attached may also denote a group selected fromcyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,dioxanyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl,isoquinolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide,thiomorpholinyl-S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl,dihydrofuranyl, dihydropyranyl and piperazinyl, which may be substitutedindependently of one another by 1, 2 or 3 substituents R^(6.1), R^(5.1)denotes (a) H, (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁶ independently of oneanother denote (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₆-cycloalkyl, (b) an aryl group optionally substituted by 1, 2 or 3substituents R^(6.2), wherein the substituents R^(6.2) may be identicalor different, (c) a heteroaryl group optionally substituted by 1, 2 or 3substituents R^(6.2), wherein the substituents R^(6.2) may be identicalor different, (d) a heterocyclic group optionally substituted by 1, 2 or3 substituents R^(6.2), wherein the substituents R^(6.2) may beidentical or different, R^(6.1) denotes (a) H, halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —CO₂R⁷, —C(O)NR⁸R⁹,—SO₂—NR⁸R⁹, —N(R⁸)—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹, —O—C(O)—R⁷ or (c)a C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(6.2) denotes (a) halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—R⁷, —O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —S(O)_(m)—R⁸,—CN, —O—C(O)—R⁷ or (c) a C₁₋₃-alkyl group wherein each methylene groupis substituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁷ denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may besubstituted by a group R^(7.1), or (c) a C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(7.1)denotes halogen, HO— or C₁₋₆-alkyl-O—, R⁸ denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, wherein the groups may beunsubstituted or substituted by halogen, HO— or C₁₋₆-alkyl-O—, or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R⁹ denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl,heteroaryl, or benzyl, wherein the groups may be unsubstituted orsubstituted by halogen, HO— or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, orR⁸ and R⁹ together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R⁷, wherein the substituents R⁷ are independent of oneanother, m denotes one of the numbers 0, 1 or 2 and s denotes one of thenumbers 1, 2 or 3, or a tautomer or salt thereof.
 4. A compound of theformula I according to claim 1, wherein R¹ denotes a group of generalformulae

wherein Q-T denotes C(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶), N═C(R⁶), C(R⁶)₂—C(═O),C(═O)—C(R⁶)₂, C(R⁶)₂—S(O)_(m) or C(R⁶)₂—N(R⁶), while in a groupC(R⁶)₂—C(R⁶)₂, C(R⁶)═C(R⁶) or C(R⁶)₂—N(R⁶) contained in Q-T in each casea group R⁶ together with an adjacent group R⁶ and the atoms to whichthese groups are attached may also denote a group selected fromcyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, phenyl,naphthyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, morpholinyl, pyrrolidinyl, piperidinyl,tetrahydrofuranyl, tetrahydropyranyl and piperazinyl, which may besubstituted independently of one another by 1, 2 or 3 substituentsR^(6.1), R^(5.1) denotes (a) H, (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,(c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁶ denotes (a) H, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) an aryl group optionally substituted by 1, 2 or 3substituents R^(6.2), wherein the substituents R^(6.2) may be identicalor different, (c) a heteroaryl group optionally substituted by 1, 2 or 3substituents R^(6.2), wherein the substituents R^(6.2) may be identicalor different, (d) a heterocyclic group optionally substituted by 1, 2 or3 substituents R^(6.2), wherein the substituents R^(6.2) may beidentical or different, R^(6.1) denotes (a) H, halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—C₁₋₆-alkylene-NR⁸R⁹, —O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹,—SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN, —NR⁸R⁹, —O—C(O)—R⁷ or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(6.2) denotes (a) halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—R⁷, —O—(CH₂)_(s)—OR⁷, —CO₂R⁷, —S(O)_(m)—R⁸, —CN,—O—C(O)—R⁷ or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁷ denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may besubstituted by a group R^(7.1), or (c) a C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(7.1)denotes halogen, HO— or C₁₋₆-alkyl-O—, R⁸ denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, wherein the groups may beunsubstituted or substituted by halogen, HO— or C₁₋₆-alkyl-O—, or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R⁹ denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl,heteroaryl, or benzyl, wherein the groups may be unsubstituted orsubstituted by halogen, HO— or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, orR⁸ and R⁹ together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R⁷, wherein the substituents R⁷ are independent of oneanother, m denotes one of the numbers 0, 1 or 2 and s denotes one of thenumbers 1, 2 or 3, or a tautomer or salt thereof.
 5. A compound of theformula I according to claim 1, wherein R¹ denotes a group of formulae

wherein R^(5.1) denotes (a) H, (b) C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁶ independently of oneanother denote (a) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) a phenyl groupoptionally substituted by 1, 2 or 3 substituents R^(6.2), wherein thesubstituents R^(6.2) may be identical or different, (c) a heteroarylgroup optionally substituted by 1, 2 or 3 substituents R^(6.2) which isselected from among benzimidazole, benzothiophene, furan, imidazole,indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene and triazole, wherein thesubstituents R^(6.2) may be identical or different, (d) a heterocyclicgroup optionally substituted by 1, 2 or 3 substituents R^(6.2), whereinthe substituents R^(6.2) may be identical or different, R^(6.1) denotes(a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) —O—C₁₋₆-alkylene-NR⁸R⁹,—O—R⁷, —CO₂R⁷, —C(O)—NR⁸R⁹, —SO₂—NR⁸R⁹, —NR⁸—SO₂—R⁹, —S(O)_(m)—R⁸, —CN,—NR⁸R⁹, —O—C(O)—R⁷ or (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(6.2)denotes (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) —O—R⁷,—O—(CH₂)_(s)—O—R⁷, —CO₂R⁷, —S(O)_(m)—R⁸, —CN, —O—C(O)—R⁷ or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R⁷ denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl,heteroaryl, benzyl which may be substituted by a group R^(7.1), or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(7.1) denotes HO— or C₁₋₆-alkyl-O—, R⁸ denotes (a) H,(b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups may beunsubstituted or substituted by halogen, HO— or H₃C—O—, R⁹ denotes (a)H, (b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups may beunsubstituted or substituted by halogen, HO— or H₃C—O—, or R⁸ and R⁹together may also form a ring which is selected from among azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the ringmay be unsubstituted or substituted by a substituent R⁷, m denotes oneof the numbers 0, 1 or 2, and s denotes one of the numbers 1, 2 or 3, ora tautomer or salt thereof.
 6. A compound of the Compounds of generalformula I according to claim 1, wherein R¹ denotes

or a tautomer or salt thereof.
 7. A compound of the formula I accordingto claim 1, wherein or a tautomer or salt thereof.
 8. A compound of theformula I according to claim 1, wherein R³ denotes (a) H, (b)C₁₋₆-alkyl, (c) a C₃₋₆-cycloalkyl group substituted by one or two groupsR^(3.2), (d) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.2) independently of oneanother denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁴ denotes (a) H, (b)C₁₋₆-alkylene-R^(4.1), (c) a C₃₋₆-cycloalkyl group substituted by one ortwo groups R^(4.2), (d) a C₅₋₇-cycloalkenyl group substituted by one ortwo groups R^(4.2), (e) an aryl group substituted by one or two groupsR^(4.2), (f) a C₅₋₇-cycloalkyl group which may be fused to an aryl groupand is additionally substituted by one or two groups R^(4.2), or (g) aheteroaryl group substituted by one or two groups R^(4.2), R^(4.1)denotes (a) H, (b) a phenyl group substituted by the groups R^(4.1.1)and R^(4.1.2), (c) a heteroaryl group substituted by the groupsR^(4.1.1) and R^(4.1.2), R^(4.1.1) denotes (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —NR^(4.1.1.1)R^(4.1.1.2),—S—C₁₋₃-alkyl, —NR^(4.1.1,1-)C(O)—C₁₋₃-alkyl,—C(O)—NR^(4.1.1.1)R^(4.1.1.2), —C(O)—O—R^(4.1.1.3), (c) a C₁₋₃-alkyl or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(4.1.1.1) denotes H, C₁₋₃-alkyl, R^(4.1.1.2) denotesH, C₁₋₃-alkyl, or R^(4.1.1.1) and R^(4.1.1.2) together with the nitrogenatom to which they are bound may also denote a group selected frommorpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl andazetidinyl, R^(4.1.1.3) denotes H, C₁₋₃-alkyl, R^(4.1.2) denotes (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or R^(4.2) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —NR^(4.2.1)R^(4.2.2),—S—C₁₋₃-alkyl, —NR^(4.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.2.1)R^(4.2.2),—C(O)—O—R^(4.2.3), (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(4.2.1)denotes H, C₁₋₃-alkyl and R^(4.2.2) denotes H, C₁₋₃-alkyl, or R^(4.2.1)and R^(4.2.2) together with the nitrogen atom to which they are boundmay also denote a group which is selected from among morpholinyl,thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl andazetidinyl, and which may additionally be substituted by one or twogroups selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,R^(4.2.3) denotes H, C₁₋₃-alkyl, R³ and R⁴ together with the nitrogenatom to which they are bound denote: (a) a saturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4), (b) a saturated 5-,6- or 7-membered heterocyclic group which is substituted at two adjacentcarbon atoms by in each case a group R^(4.3) and R^(4.4), (c) asaturated 5-, 6- or 7-membered heterocyclic group which is substitutedat a carbon atom by a group R^(4.3) or by two groups R^(4.3) and R^(4.4)and is additionally fused to a 5-, 6- or 7-membered cycloalkyl orheterocyclyl group, while the fused-on cycloalkyl or heterocycyl groupis substituted by 1, 2 or 3 groups R^(4.5), (d) a monounsaturated 5-, 6-or 7-membered heterocyclic group which is substituted at a carbon atomby a group R^(4.3) or by two groups R^(4.3) and R^(4.4) and isadditionally fused to a phenyl group, while the fused-on phenyl group issubstituted by 1, 2 or 3 groups R^(4.5), (e) a monounsaturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4) and is additionallyfused to a 5- or 6-membered heteroaryl group, while the fused-onheteroaryl group is substituted by 1, 2 or 3 groups R^(4.5), or (f) aheteroaryl group which is substituted at 1, 2 or 3 carbon atoms by agroup R^(4.5), R^(4.3) denotes H, C₁₋₃-alkyl, phenyl,—C₁₋₃-alkylene-R^(4.3.1), C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F,—O—C₁₋₃-alkyl, —OH, —CN R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O—,cyclopropyl, C₁₋₃-alkyl-O—C(O)—, CN, —NH₂, (C₁₋₄-alkyl)-NH—,(C₁₋₄-alkyl)₂N, heterocyclyl, R^(4.4) denotes (a) H, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl or (b) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(4.3) andR^(4.4) together with the carbon atom to which they are attached mayalso denote a C₃₋₆-cycloalkyl-, C₅₋₆-cycloalkenyl- or heterocyclylgroup, R^(4.5) independently of one another denote (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN, —C(O)—O—R^(4.5.1),—C(O)—NR^(4.5.2)R^(4.5.3), (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, (d)phenyl, R^(4.5.1) denotes H, C₁₋₃-alkyl, R^(4.5.2) denotes H, C₁₋₃-alkyland R^(4.5.3) denotes H, C₁₋₃-alkyl, or a tautomer or salt thereof.
 9. Acompound of the formula I according to claim 1, wherein R³ denotes (a)H, (b) C₁₋₆-alkyl, (c) a C₃₋₆-cycloalkyl substituted by one or twogroups R^(3.2), or (d) a C₁₋₃-alkyl group wherein each methylene groupis substituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.2) independently of oneanother denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁴ denotes (a) H, (b)C_(1i-6)-alkylene-R^(4.1), (c) a C₃₋₆-cycloalkyl group substituted byone or two groups R^(4.2), (d) a C₅₋₇-cycloalkenyl group substituted byone or two groups R^(4.2), (e) an aryl group substituted by one or twogroups R^(4.2), (f) a C₅₋₆-cycloalkyl group which may be fused to aphenyl group and which is additionally substituted by one or two groupsR^(4.2), R^(4.1) denotes (a) H, (b) a phenyl group substituted by thegroups R^(4.1.1.3) and R^(4.1.2), R^(4.1.1) denotes (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN, —C(O)—O—R^(4.1.13), (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.1.1.3) denotes H,C₁₋₃-alkyl, R^(4.1.2) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, or R^(4.2)independently of one another denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl, —CN, —O—C(O)—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R³ and R⁴ together with the nitrogen atom to which theyare bound denote: (a) a saturated 5- or 6-membered heterocyclic groupwhich is substituted at a carbon atom by a group R^(4.3) or by twogroups R^(4.3) and R^(4.4), (b) a saturated 5- or 6-memberedheterocyclic group which is substituted at two adjacent carbon atoms bya group R^(4.3) and R^(4.4) in each case, (c) a saturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4) and is additionallyfused to a 5-, 6- or 7-membered cycloalkyl or heterocyclyl group, whilethe fused-on cycloalkyl or heterocycyl group is substituted by 1, 2 or 3groups R^(4.5), (d) a monounsaturated 5-, 6- or 7-membered heterocyclicgroup which is substituted at a carbon atom by a group R^(4.3) or by twogroups R^(4.3) and R^(4.4) and is additionally fused to a phenyl group,while the fused-on phenyl group is substituted by 1, 2 or 3 groupsR^(4.5), (e) a monounsaturated 5-, 6- or 7-membered heterocyclic groupwhich is substituted at a carbon atom by a group R^(4.3) or by twogroups R^(4.3) and R^(4.4) and is additionally fused to a 5- or6-membered heteroaryl group, while the fused-on heteroaryl group issubstituted by 1, 2 or 3 groups R^(4.5) and is selected from among

(f) a heteroaryl group which is substituted at 1, 2 or 3 carbon atoms byin each case a group R^(4.5), R^(4.3) denotes H, C₁₋₃-alkyl, phenyl,—C₁₋₃-alkylene-R^(4.3.1), C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F,—O—C₁₋₃-alkyl, —OH, —CN R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O,cyclopropyl, C₁₋₃-alkyl-O—C(O)—, CN, —NH₂, (C₁₋₄-alkyl)-NH—,(C₁₋₄-alkyl)₂N—, morpholinyl, thiomorpholinyl, piperidinyl,pyrrolidinyl, azetidinyl, R^(4.4) denotes (a) H, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl or (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(4.3) andR^(4.4) together with the carbon atoms to which they are attached mayalso denote a C₃₋₆-cycloalkyl or heterocyclyl group, and R^(4.5)independently of one another denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl, —NH₂, —CN, (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, or(d) denotes phenyl, or a tautomer or salt thereof.
 10. A compound of theformula I according to claim 1, wherein R³ denotes (a) H, (b)C₁₋₆-alkyl, (c) a C₃₋₆-cycloalkyl group substituted by one or two groupsR^(3.2), or (d) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.2) independently of oneanother denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R⁴ denotes (a) H, (b)C₁₋₆-alkylene-R^(4.1), (c) a C₃₋₆-cycloalkyl group substituted by one ortwo groups R^(4.2), (d) a C₅₋₇-cycloalkenyl group substituted by one ortwo groups R^(4.2), (e) a phenyl group substituted by one or two groupsR^(4.2), (f) a C₅₋₆-cycloalkyl group which may be fused to a phenylgroup and is additionally substituted by one or two groups R^(4.2),R^(4.1) denotes (a) H, (b) a phenyl group substituted by the groupsR^(4.1.1) and R^(4.1.2), R^(4.1.1) denotes (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN, —C(O)—O—R^(4.1.1.3), (c) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.1.1.3) denotes H,C₁₋₃-alkyl, R^(4.1.2) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, or R^(4.2)denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN, (c) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R³ and R⁴ together withthe nitrogen atom to which they are attached denote: (a) a saturated 5-or 6-membered heterocyclic group, which is selected from amongpiperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl,pyrrolidinyl and pyrrolidinonyl, and which is substituted at a carbonatom by a group R^(4.3) or by two groups R^(4.3) and R^(4.4), (b) asaturated 5- or 6-membered heterocyclic group, which is selected fromamong piperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl,piperazinyl, pyrrolidinyl and pyrrolidinonyl, and which is substitutedat two adjacent carbon atoms by a group R^(4.3) and R^(4.4) in eachcase, (c) a saturated 5-, 6- or 7-membered heterocyclic group, which isselected from among piperidinyl, piperidinonyl, morpholinyl,thiomorpholinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl, azepanyl,diazepanyl, diazepanonyl and oxazepanyl, and which is substituted at acarbon atom by a group R^(4.3) or by two groups R^(4.3) and R^(4.4) andis additionally fused to a 5-, 6- or 7-membered cycloalkyl orheterocyclyl group, which is selected from among piperidinyl,piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl,pyrrolidinonyl, azepanyl, diazepanyl, diazepanonyl and oxazepanyl, whilethe fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2 or3 groups R^(4.5), (d) a monounsaturated 5-, 6- or 7-memberedheterocyclic group, which is selected from among

 and which is substituted at a carbon atom by a group R^(4.3) or by twogroups R^(4.3) and R^(4.4) and is additionally fused to a phenyl group,while the fused-on phenyl group is substituted by 1, 2 or 3 groupsR^(4.5), (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group,which is selected from among

 and which is substituted at a carbon atom by a group R^(4.3) or by twogroups R^(4.3) and R^(4.4) and is additionally fused to a 5- or6-membered heteroaryl group, while the fused-on heteroaryl group issubstituted by 1, 2 or 3 groups R^(4.5) and is selected from among

(f) a heteroaryl group, which is selected from among indole, isoindole,azaindole, indazole and benzimidazole, and which is substituted at 1, 2or 3 carbon atoms by a group R^(4.5), R^(4.3) denotes H, C₁₋₃-alkyl,phenyl, —C₁₋₃-alkylene-R^(4.3.1), C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F,—O—C₁₋₃-alkyl, —OH, —CN, R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O—,cyclopropyl, C₁₋₃-alkyl-O—C(O)—, CN, —NH₂, (C₁₋₄-alkyl)-NH—,(C₁₋₄-alkyl)₂N—, morpholinyl, thiomorpholinyl, piperidinyl,pyrrolidinyl, azetidinyl, R^(4.4) denotes (a) H, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl or (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(4.3) andR^(4.4) together with the carbon atom to which they are attached alsodenote a C₃₋₆-cycloalkyl group or a heterocyclyl group which is selectedfrom among azetidinyl, pyrrolidinyl, piperidinyl and azepanyl, andR^(4.5) independently of one another denotes (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or (d) phenyl, or a tautomer or salt thereof.
 11. Acompound of the formula I according to claim 1, wherein R³ denotes (a)H, (b) C₁₋₃-alkyl, (c) a C₁₋₃-alkyl group wherein each methylene groupis substituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, and R⁴ denotes H or a groupselected from

R³ and R⁴ together with the nitrogen atom to which they are attacheddenote a group selected from

or a tautomer or salt thereof.
 12. A compound of the formula I accordingto claim 1, wherein R³ and R⁴ together with the nitrogen atom to whichthey are attached denote a monounsaturated 5-membered heterocyclicgroup, which is substituted at a carbon atom by a group R^(4.3) or bytwo groups R^(4.3) and R^(4.4) and is additionally fused to a phenylgroup, while the fused-on phenyl group is substituted by 1, 2 or 3groups R^(4.5), R^(4.3) denotes H, C₁₋₃-alkyl, phenyl,—C₁₋₃-alkylene-R^(4.3.1), C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F,—O—C₁₋₃-alkyl, —OH, —CN, R^(4.3.1) denotes H, HO, C₁₋₃-alkyl-O—,C₁₋₃-alkyl-O—C(O)—, cyclopropyl, CN, —NH₂, (C₁₋₄-alkyl)-NH—,(C₁₋₄-alkyl)₂N—, morpholinyl, thiomorpholinyl, piperidinyl,pyrrolidinyl, azetidinyl, R^(4.4) denotes (a) H, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl or (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, or R^(4.3)and R^(4.4) together with the carbon atom to which they are attachedalso denote a C₃₋₆-cycloalkyl group or a heterocyclyl group which isselected from among azetidinyl, pyrrolidinyl, piperidinyl and azepanyl,and R^(4.5) independently of one another denotes (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN, NO₂, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or (d) phenyl, or a tautomer or salt thereof.
 13. Acompound of the formula I according to claim 1, wherein R³ and R⁴together with the nitrogen atom to which they are attached denote agroup of general formula IIIa or IIIb

R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN, R^(4.3.1)denotes H, HO, C₁₋₃-alkyl-O, C₁₋₃-alkyl-O—C(O), CN, —NH₂,(C₁₋₄-alkyl)-NH, (C₁₋₄-alkyl)₂N, morpholinyl, thiomorpholinyl,piperidinyl, pyrrolidinyl, azetidinyl, R^(4.4) denotes (a) H,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkylgroup wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, or R^(4.3) and R^(4.4) together with the carbon atom to whichthey are attached also denote a C₃₋₆-cycloalkyl group or a heterocyclylgroup which is selected from among azetidinyl, pyrrolidinyl, piperidinyland azepanyl, and R^(4.5) independently of one another denotes (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN, NO₂, (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or (d) phenyl, or a tautomeror salt thereof.
 14. A compound of the formula I according to claim 1,wherein R³ and R⁴ together with the nitrogen atom to which they areattached denote a group selected from

or bases or a tautomer or salt thereof.
 15. A compound of the formula Iaccording to claim 1, wherein U—V—X denotes a group selected from—N═N—(C—R¹²)═, —N═(C—R¹¹)—N═, —N═(C—R¹¹)—(C—R¹²)═,—(N-oxide)=(C—R¹¹)—(C—R¹²)═, —(C—R¹⁰)═N—N═, —(C—R¹⁰)═N—(C—R¹²)═,—(C—R¹⁰)═N(oxide)-(C—R¹²)═, —(C—R¹⁰)═(C—R¹¹)—N═,—(C—R¹⁰)═(C—R¹¹)—(N-oxide)=, and —(C—R¹⁰)═(C—R¹¹)—(C—R¹²)═, R¹⁰ denotesH, —CN, R¹¹ denotes H, —NR^(11.1)R^(11.2) or —O—C₁₋₃-alkyl, R^(11.1)denotes H or C₁₋₆-alkyl, R^(11.2) denotes H or —SO₂—C₁₋₃-alkyl, R¹²denotes H, —CN and Y denotes N or CH, or bases or a tautomer or saltthereof.
 16. A compound of the formula I according to claim 1, whereinthe ring

denotes a group selected from

or a tautomer or salt thereof.
 17. A compound of the formula I accordingto claim 1, wherein R¹ denotes a group selected from

R² denotes H, R³ denotes (a) H, (b) C₁₋₃-alkyl, (c) a C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, andR⁴ denotes H or a group selected from

R³ and R⁴ together with the nitrogen atom to which they are attacheddenote a group selected from

and the ring

denotes a group selected from

or bases or a tautomer or salt thereof.
 18. A compound of the formula Iaccording to claim 1, wherein R¹ denotes a group selected from

R³ and R⁴ together with the nitrogen atom to which they are attacheddenote a group selected from

and the ring

denotes a group selected from

or a tautomer or salt thereof.
 19. A compound of the formula I accordingto claim 1, selected from the group consisting of No. Structure (1)

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or a tautomer or salt thereof.
 20. A physiologically acceptable salt ofa compound according to any one of claims 1-19.
 21. A pharmaceuticalcomposition comprising a compound according to any one of claims 1-19,or a physiologically acceptable salt thereof, and a carrier or diluent.22. A method for treating migraine and cluster headache which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound according to any one of claims 1-19, or aphysiologically acceptable salt thereof. 23-25. (canceled)